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Keywords:

  • mammalian target of rapamycin;
  • everolimus;
  • temsirolimus;
  • rash;
  • adverse event

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND:

Dermatologic adverse events stemming from anticancer therapies have become an increasingly frequent clinical problem. Inhibitors of mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus, have been associated with a high rate of skin eruptions, but their clinical and histopathologic characteristics have not been explored.

METHODS:

A retrospective analysis of patients who were referred to the Dermatology Service for diagnosis and management of rash in the setting of therapy with the mTOR inhibitors everolimus and temsirolimus was performed. The parameters that were studied included the time to onset, clinical presentation at the time of dermatologic evaluation, associated symptoms, evolution, results of microbiologic studies, concomitant medications, the need for dose reduction and/or treatment interruption because of rash, and routine histopathology.

RESULTS:

In total, 13 patients were analyzed. Most rashes were mild (grade 1; 31%) and moderate (grade 2; 54%) in severity, and grade 3 rashes were observed only in 2 patients (15%). The trunk was the most frequently affected region (77%), with the scalp (23%), face (38%), neck (54%), and extremities (69%) also commonly involved. Erythematous papules and pustules constituted the predominant primary lesion morphology (62%). No unique or uniform histopathologic reaction pattern was observed. The most common reaction pattern was that of a mixed, spongiotic interface and perivascular dermatitis, which was observed in 7 of 11 patients (63%).

CONCLUSIONS:

Although mTOR inhibitors may commonly induce erythematous papules and pustules, they are associated with a spectrum of lesion morphologies and a variety of histopathologic findings. Further clinicohistologic correlation studies are needed. Cancer 2012. © 2012 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

The phosphoinositide 3-kinase inhibitor (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway is a critical intracellular signaling cascade that drives carcinogenesis when abnormally activated. Since the identification of rapamycin (sirolimus), several derivatives (rapalogues) have been developed, including temsirolimus, everolimus, and ridaforolimus. Because of their increased solubility and antiproliferative properties, everolimus and temsirolimus have been approved by the US Food and Drug Administration for the treatment of multiple malignancies.1 All of these first-generation mTOR inhibitors preferentially target mTOR complex-1 and share a similar adverse event (AE) profile. Dermatologic AEs, including stomatitis, and extracutaneous side effects, such as thrombocytopenia, hyperglycemia, hyperlipidemia, and gastrointestinal toxicities, are frequent.2

A rash is observed with rapalogues (everolimus: all grades, 25%; grade ≥3, <1%; temsirolimus: all grades, 46%; grade ≥3, 3%).3, 4 Clinically, the rash has been described as erythematous maculopapular, acneiform, and eczematoid.2 Whereas clinical and histopathologic alterations of the pilosebaceous apparatus, predominantly manifesting as acne, have been described in patients who receive treatment with sirolimus,5 to our knowledge, the clinical characteristics of rash induced by everolimus and temsirolimus have not been characterized. Furthermore, the underlying histopathologic alterations are unknown, precluding rationally developed management strategies. In the current study, we analyzed the clinical and histopathologic features of rash induced by everolimus and temsirolimus.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

We conducted a retrospective analysis of patients who were referred to the Dermatology Service for diagnosis and management of rash induced by the mTOR inhibitors everolimus and temsirolimus. We only included patients who received treatment at the approved dose levels (intravenous temsirolimus 25 mg weekly and oral everolimus 10 mg daily). Because it has been reported only rarely that bevacizumab causes skin toxicity,6, 7 patients who received rapalogues in combination with this agent were also analyzed. The parameters that we studied included the time to onset, clinical presentation at the time of dermatologic evaluation, associated symptoms, evolution, results from microbiologic studies, concomitant medications, and the need for dose reduction and/or treatment interruption because of rash. Routine histopathology (hematoxylin and eosin-stained sections for formalin-fixed and paraffin-embedded skin biopsies) was reviewed by 3 dermatopathologists (B.H.T., K.J.B., and M.P.P.). The predominant histopathologic pattern in each biopsy was described. The severity of the rash was graded according to the Common Terminology Criteria for Adverse Events (version 4.0; National Cancer Institute, Bethesda, Md).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

In total, 13 patients were included (9 men and 4 women; 13 Caucasians and 1 African American). The median age was 65 years (range, 35-76 years). Six patients (46%) patients received treatment with everolimus, 5 patients (39%) received treatment with temsirolimus, and 2 patients (15%) received treatment with temsirolimus in combination with intravenous bevacizumab 10 mg biweekly. The underlying cancer diagnosis was advanced renal cell carcinoma in 11 patients (85%), uterine carcinoma in 1 patient (7.5%), and pancreatic neuroendocrine tumor in 1 patient (7.5%). Clinically, the rash was definitely attributed to mTOR inhibitors in all patients. Five of 13 patients reported a history of cutaneous reactions to a variety of substances, including oral antibiotics, opioids, shellfish, paper tape, and latex.

The onset of the rash occurred within the first month of therapy (as early as 1 week) in 11 patients (85%). In 2 patients (15%), the rash manifested after 2 to 3 months of treatment. Pruritus was the most common symptom, affecting 12 patients (92%). Most cases were mild (grade 1, 31%) and moderate (grade 2, 54%), with severe (grade 3) rash observed in 2 patients (15%). Both patients with grade 3 rash had a papulopustular appearance. The lesions covered >30% of the body surface area and were associated with severe pruritus. Erythematous papules (Fig. 1A) constituted the predominant primary lesion in 8 patients. The trunk was the most frequently affected region (77%), and the scalp (23%), face (38%), neck (54%), and extremities (69%) also commonly were involved. Among the 8 patients who had erythematous papular lesions, 5 patients (63%) also had pustules on an erythematous base (Fig. 1B) that most often involved the scalp, face, neck, and upper trunk. Erythematous nodules that affected the unilateral neck were observed in 1 patient (Fig. 2). There was a tendency for the rash to coalesce into larger erythematous plaques, particularly affecting the extremities (Fig. 3). Three patients presented with erythematous plaques (psoriasiform or eczematous-appearing) in the absence of distinct papular and/or pustular lesions that affected the trunk and extremities and were limited to the face or to a lateral aspect of a lower extremity. A morbilliform, erythematous eruption on the trunk and upper extremities was observed in 1 patient. No comedonal (acne) lesions were noted.

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Figure 1. These photographs show (A) erythematous papular lesions and (B) pustules on an erythematous base.

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Figure 2. These are erythematous nodules affecting the unilateral neck.

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Figure 3. (A,B) These are views of coalescence of a rash into larger erythematous plaques on the extremities.

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Eleven patients underwent skin biopsies. The most common reaction pattern was that of a mixed spongiotic interface and perivascular dermatitis, which was observed in 7 of 11 patients (63%). Mixed perifollicular suppurative, and eczematous patterns were observed in 2 patients (Table 1). The histology of the rash depicted in Figure 1A revealed psoriasiform and spongiotic dermatitis with a superficial dermal eosinophilic infiltrate. Similarly, the rash depicted in Figure 3B was described as spongiotic dermatitis with eosinophils. The indurated, nodular lesions depicted in Figure 2 demonstrated superficial and deep perivascular and interstitial, mixed-cell infiltrates, including eosinophils and neutrophils, with vasculopathic changes, compatible with a drug reaction.

Table 1. Histologic Characteristics of Rash and the Corresponding Lesion Morphology
PatientmTOR InhibitorDrug AllergyEczematousPerivascular InflammationSpongiosisInterface DermatitisVasculopathyEosinophilsFollicularOtherAnatomic Location of Skin BiopsyMorphology of the Biopsied LesionMorphology of the RashPeripheral Eosinophilia (Normal, 0%-7%), %
  1. Abbreviations: mTOR, mammalian target of rapamycin; NA, not available; NKDA, no known drug allergies.

  2. Two patients did not have skin biopsies performed. Clinically, one patient had erythematous papules with scattered pustules and one patient had erythematous, eczematous-appearing plaques.

1TemsirolimusNKDA  X XX  Left upper armErythematous plaqueErythematous papules with scattered pustules12.1
3TemsirolimusPenicillin X XX   BackErythematous maculopapularErythematous maculopapules9.5
6TemsirolimusPenicillin, dilaudid, oxycontin X   X  Left lower extremityErythematous plaqueErythematous papules6
10TemsirolimusNKDA  X  X  Right upper extremityErythematous plaqueErythematous papules with scattered pustules9.4
2Temsirolimus and bevacizumabAmoxicillin x X    ChestErythematous papuleErythematous papules2
8Temsirolimus and bevacizumabNKDA x   X Superficial and deep, arthropod-likeLeft neckErythematous noduleErythematous nodules5
11EverolimusNKDA  XX     Erythematous plaqueErythematous plaques3
4EverolimusNKDA   X  XSuppurativeLeft flankErythematous papuleErythematous papules with scattered pustules1.2
9EverolimusNKDA      XSuppurativeRight shoulderErythematous papuleErythematous papules with scattered pustulesNA
5EverolimusNKDAX       Left lower extremityErythematous plaqueErythematous plaques3.8
7EverolimusNKDAX      Plasma cellsBackErythematous plaqueErythematous papules5.5

Permanent discontinuation of therapy because of rash was necessary in 2 patients (15%). The first patient had a grade 3 rash and ultimately required drug discontinuation because of severe pruritus that did not improve with topical and/or systemic therapies. The second patient required frequent drug interruptions and dose reductions because of severe pruritus and ultimately had disease progression identified. In 3 patients (23%), interruption of mTOR inhibitors with subsequent dose reduction was required. In all 3 patients, this resulted in marked improvement or complete resolution of the rash within approximately 1 to 2 months and as early as 1 week in 1 patient. Among those who continued to receive standard doses of mTOR inhibitors and received topical and/or systemic therapy for the rash, the time to resolution ranged from 1 week to 2 months.

Topical interventions included moderate-high-potency topical corticosteroids (eg, fluocinonide, clobetasol) alone or in combination with topical antibiotics (eg, clindamycin). Systemic therapies consisted of doxycycline 100 mg twice daily and, for severe cases, a corticosteroid taper (methylprednisolone dose pack or prednisone 0.5 mg/kg). For suspected secondary bacterial superinfection, empiric cephalosporin antibiotics, sulfamethoxazole/trimethoprim, doxycycline, and/or topical clindamycin were used. Swab cultures obtained in 6 patients were all negative. For pruritus associated with rash, topical potent corticosteroids, antipruritic lotions, and systemic antihistamines (eg, hydroxizine, diphenhydramine) were used followed by doxepin in patients who had refractory pruritus.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Rash induced by mTOR inhibitors has distinct clinical and histologic findings that differ from other targeted agents. It has been reported that sirolimus causes acne-like lesions and maculopapular exanthems in up to 45% and 3% to 68% of treated patients, respectively.5, 8 Temsirolimus has been associated with both maculopapular rashes (50%) and acne-like rashes (38%),9 and everolimus induced rash/desquamation in 28% of patients10 and acne-like rashes in 12% to 34% of patients.10, 11 In general, everolimus-induced and temsirolimus-induced maculopapular exanthems manifest within the first month of therapy and affect the face, neck, and upper trunk.9-12

In our current study, erythematous papules and pustules constituted the predominant primary lesion morphology. Consistent with previous reports,13 papulopustular rash typically affected areas rich in sebaceous glands, including the upper trunk (100%), neck (75%), face (50%), and scalp (38%), with frequent involvement of extremities (75%). In patients who had a papulopustular rash, histologic examination of pustular lesions revealed a suppurative folliculitis; whereas, in patients who had erythematous papules or a maculopapular rash (eg, hypersensitivity type), perivascular inflammation with eosinophils and an interface dermatitis constituted the predominant pattern. Atypical presentations with unilateral cervical neck erythematous nodules, like the patient depicted in Figure 2, have been reported in sirolimus-treated patients.5, 14 Twenty-three percent of our patients presented with erythematous plaques, particularly on the upper extremities, which clinically appeared eczematous or psoriasiform. Histologically, psoriasiform and spongiotic dermatitis was observed, a pattern that is common in eczematous (allergic) processes. Eczematous types of cutaneous reactions have been reported previously in a minority of patients who received sirolimus and temsirolimus.9, 14 In some patients, confluent plaques were evident in antecubital and popliteal fossae, typical of eczematous-type dermatoses. This presentation was described previously with temsirolimus and was characterized histologically by spongiotic dermatitis with eosinophils,15 consistent with our findings.

Currently, the etiology of a rash in the setting of mTOR inhibitors remains unclear. Inhibition of the PI3K-Akt-mTOR pathway by rapalogues may contribute through the inhibition of epidermal growth factor-driven cell transformation.16 In addition, it has been demonstrated that mouse skin keratinocytes with diminished Akt/mTOR activity are smaller in size and have diminished protein translation, suggesting an induction of G1 growth arrest.17 The nonspecific histology suggests that there may be a delayed-type hypersensitivity component, although the antigens that may drive this process are unknown.

The preferred approach to treating these skin lesions is based on clinical phenotype. Initial therapy for grade 1 papulopustular rash includes a topical low-moderate-strength steroid and topical antibiotics. For grade 3 or intolerable grade 2 rashes, oral antibiotics for 2 to 4 weeks are recommended. Treatment for grade 1 maculopapular rashes includes topical low-moderate-strength steroids and oral antihistamines. Oral steroids, dose modifications, or drug interruption may be required for grade 3 or intolerable grade 2 rashes.

It was demonstrated previously that an increased severity of rash corresponds with improved drug response to treatment with the epidermal growth factor receptor inhibitor cetuximab.18 However, to our knowledge, this association has yet to be evaluated in patients who received treatment with mTOR inhibitors. The small number of patients included in our current retrospective series, the different timing of mTOR inhibitor treatment (first line, second line, etc), and the inclusion of multiple mTOR inhibitors (everolimus, temsirolimus) prevent us from drawing any conclusions with regard to an association between rash and outcome of mTOR inhibitor therapy.

We have demonstrated the spectrum of cutaneous manifestations associated with the first-generation of mTOR inhibitors, among which papulopustular lesions constitute the most common morphology. Frequently associated pruritus may have an impact on patients' quality of life. Future prospective investigations directed at elucidating the underlying pathophysiology of these rashes are needed to facilitate the development of evidence and mechanism-based treatment strategies.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

M.E.L. is supported by a Career Development Award from the Dermatology Foundation.

CONFLICT OF INTEREST DISCLOSURES

J.R.M. receives research funding from Pfizer, Novartis, BristolMeyersSquib, and Aveo Pharmaceuticals and is a consultant for Pfizer. D.R.F. is a consultant for Novartis. D.R.L. is on the advisory boards of Novartis and Pfizer. M.E.L. has a consultant or advisory role with Amgen, Bayer, BI, BMS, Genentech, Genzyme, GSK, Hara, Imclone, Lilly, Onyx, OSI, Pfizer, Roche, and Wyeth; he also receives research funding from Hana Biosciences and Onyx Pharmaceuticals.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES