The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus: A systematic review of the literature and meta-analysis

doi:10.1016/j.ejca.2011.11.028

European Journal of Cancer

Volume 48, Issue 3, February 2012, Pages 340-346

https://doi.org/10.1016/j.ejca.2011.11.028 Get rights and content

Abstract

Objective

We conducted a systematic review of the literature and performed a meta-analysis to determine the risk of developing skin rash and stomatitis among patients receiving temsirolimus.

Methods

Databases from PubMed and Web of Science from January, 1998 until June, 2011 and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2011 were searched to identify relevant studies. The incidence and relative risk (RR) of skin rash and stomatitis were calculated using random-effects or fixed-effects model depending on the heterogeneity of included studies.

Results

A total of 779 patients from 10 clinical trials were included in this analysis. The overall incidence of all-grade rash was 45.8% (95% confidence interval (CI): 35.6–56.3%), with a RR of 7.6 (95% CI: 4.4–13.3; p < 0.001). The overall incidence of high-grade rash was 3.3% (95% CI: 1.9–5.6%), with a RR of 13.70 (95% CI: 0.82–227.50, p = 0.07). The overall incidence of all-grade stomatitis was 44.3% (CI: 32.1–57.1%), with a RR of 11.10, 95% CI: 5.60–22.00; p < 0.001). The overall incidence of high-grade stomatitis was 3.2% (95% CI: 1.9–5.4%), with a RR of 13.2 (95% CI: 0.80–218.50, p = 0.07).

Conclusion

There is a significant risk of developing skin rash and stomatitis in cancer patients receiving temsirolimus. The risk is independent of underlying tumour. Adequate monitoring and early intervention are recommended to prevent debilitating toxicity and suboptimal dosing.

Introduction

The mammalian target of rapamycin (mTOR) signalling pathway plays a key role in the regulation of many essential aspects of cell growth, division and angiogenesis. Dysregulation of this pathway in tumour cells is strongly associated with cancer development and progression of a number of malignancies, thereby making it an important and confirmed target in the treatment of cancer.¹ Temsirolimus, a small-molecule mTOR inhibitor, has been approved in 2007 by the United States Food and Drug Administration (US FDA) and the European Medicines Agency for treatment of advanced renal cell carcinoma (RCC).² Temsirolimus binds to an intracellular protein (FKBP-12), and the protein–drug complex binds to mTOR to inhibit its kinase activity.³ Therapy with temsirolimus inhibits the ability of mTOR in tumour cells to phosphorylate proteins that are downstream of mTOR in the phosphatidylinositol 3′ kinase–AKT signalling pathway. mTOR inhibition reduces levels of hypoxia-inducible factor (HIF)-1 and HIF-2α and VEGF in various in vitro tumour models.⁴ Inhibition of mTOR kinase results in cell cycle arrest, antiangiogenesis and apoptosis.⁵ Antiangiogenic properties are particularly significant as unregulated angiogenesis is prominent in RCC.⁴ However, this drug is associated with dermatological adverse events (AE), potentially affecting aesthetically sensitive areas in treated patients.

Commonly experienced dermatologic AE of temsirolimus include skin rash, stomatitis, acne, hair changes, pruritus, xerosis and nail changes, including paronychia.⁶ Although this adverse effect profile may be primarily dermatologic, the recognition and subsequent management of skin toxicity are critical issues because severe skin toxicity leads to morbidity and compromises the efficacy of treatment due to dose reductions or even discontinuation. Skin rash and stomatitis are among the most common AE of temsirolimus.⁷ However, the incidences of skin rash and stomatitis have not been systemically investigated and are currently unknown. We conducted a systematic review of the literature to identify published clinical trials of the mTOR inhibitor temsirolimus and performed a meta-analysis to determine the overall incidence and risk of developing skin rash and stomatitis.

Section snippets

Data source

An independent search of citations was conducted using the PubMed database (January 1998–June 2011) with ‘temsirolimus’ as a keyword. The search was limited to clinical trials. Additionally, we searched abstracts containing the term ‘temsirolimus’, that were presented at the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2011 to identify relevant clinical trials. The poster presentations of the abstracts were reviewed for complete AE data. An independent search

Search results

Our literature search yielded a total of 126 potentially relevant studies of temsirolimus. The search of PubMed identified 43 clinical studies of which 34 were excluded after review (Fig. 1). Nine original studies, including one randomised controlled Phase III, one compassionate use programme, two randomised Phase II trials of different dose levels and five single arm Phase II trials were included in a final analysis.9, 10, 11, 12, 13, 14, 15, 16, 17 Our search of ASCO abstracts yielded 83

Discussion

Our meta-analysis has demonstrated a high risk of all-grade skin rash and stomatitis with single-agent temsirolimus in patients with a variety of solid tumours. The overall incidence of all-grade and high-grade (grade ⩾3) skin rash was 45.8% (95% CI: 35.6–6.3%) and 3.3% (95% CI: 1.9–5.6%), respectively. The overall incidence of all-grade and high-grade stomatitis was 44.3% (CI: 32.1–57.1%) and 3.2% (95% CI: 1.9–5.4%). Temsirolimus was associated with significantly increased risk of all-grade rash

Conclusion

Our study has demonstrated that temsirolimus is associated with a significant risk of skin rash and stomatitis in cancer patients. Early detection and effective management may reduce this risk, which may also be modified by concurrent chemotherapy. Further studies are needed to investigate risk factors and pathogenesis and to develop effective measures for the prevention and treatment of skin toxicity.

Conflict of interest statement

M.E. Lacouture and D.R. Feldman have worked as consultants for Pfizer Inc. S. Wu serves on the advisory board and as a speaker to Pfizer Inc. B.C. Garden and C. Gomez-Fernandez have no conflicts to declare.

Acknowledgement

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

References (28)

D.A. Guertin et al.
Defining the role of mTOR in cancer
Cancer Cell
(2007)
A.L. Watters et al.
Oral complications of targeted cancer therapies: a narrative literature review
Oral Oncol
(2011)
S.S. Farag et al.
Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma
Leuk Res
(2009)
K.J. Pandya et al.
A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500)
J Thorac Oncol
(2007)
M. Gandhi et al.
Eosinophilic rash secondary to temsirolimus
Clin Genitourin Cancer
(2009)
A. Fasolo et al.
Current and future directions in mammalian target of rapamycin inhibitors development
Expert Opin Investig Drugs
(2011)
Torisel package insert:...
R.T. Abraham et al.
The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy
Clin Cancer Res
(2007)
Coppin C, Le L, Porzsolt F, Wilt T. Targeted therapy for advanced renal cell Carcinoma. Cochrane Database Syst Rev...
Staehler M, Haseke N, Khoder W, Stief CG. Profile of temsirolimus in the treatment of advanced renal cell carcinoma....

S.A. Soefje et al.

Common toxicities of mammalian target of rapamycin inhibitors

Target Oncol

(2011 Jun)

Ansell SM, Inwards DJ, Rowland KM Jr, et al. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a...

Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779;a novel mammalian...

Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced...

Cited by (44)

Cutaneous toxicities from targeted therapies used in oncology: Literature review of clinical presentation and management
2021, International Journal of Women's Dermatology
With the development of molecular targeted therapies, a wide array of dermatologic toxicities is appearing. Their prevention, recognition, and management by dermatologists is critical to ensure antineoplastic treatment continuation. The objective of this study was to provide a literature review of the most common dermatologic toxicities due to targeted therapies in oncologic patients, including their clinical presentation, prevention, and management.
Berunda Polypeptides Carrying Rapalogues Inhibit Tumor mTORC1 Better than Oral Everolimus
2020, Biomacromolecules
Rapalogues are a unique class of drugs with both cytostatic and immunosuppressive properties. Two founding members, rapamycin (Rapa) and its chemical derivative everolimus (Eve), are extremely potent, but their clinical use presents multiple challenges. Being water-insoluble, administration is restricted to the oral route, which results in a low bioavailability of <10%. Human studies of rapalogues are reported to yield a high blood to plasma ratio and poor correlation between blood concentration and dose. Moreover, treatment results in dose-limiting toxicities such as stomatitis and pneumonitis, which often leads to discontinuation of therapy. We previously reported an elastin-like polypeptide decorated with two-headed FKBP rapalogue-binding domains. Called “FAF”, this biomacromolecular drug-carrier solubilizes, retargets, and releases rapalogues within disease sites. FAF-rapalogue formulations are free of cosolvents or surfactants, which promotes their parenteral administration. In this study, subcutaneously given FAF-Rapa significantly suppressed tumor growth in a mouse model of hormone receptor positive (HR+) breast cancer, compared to an oral formulation of Eve (Affinitor). Additionally, mTOR, the pharmacological target of rapalogues, was inhibited to a greater extent in tumors of FAF-Rapa and FAF-Eve groups compared to mice that received oral Eve. No signaling suppression was detected in the liver and spleen, which were evaluated to represent off-target organs exposed to the circulating formulation.
Nanotoxicology of an Elastin-like Polypeptide Rapamycin Formulation for Breast Cancer
2020, Biomacromolecules
The clinical utility of rapamycin (Rapa) is limited by solubility, bioavailability, and side effects. To overcome this, our team recently reported an elastin-like polypeptide (ELP) nanoparticle with high affinity, noncovalent drug binding, and integrin-mediated cellular uptake. Given the scarcity of pharmacology/toxicology studies of ELP-based drug carriers, this article explores safety and efficacy of ELP-Rapa. ELP-Rapa nanoparticles tested negative for hemolysis, did not interfere in plasma coagulation nor in platelet function, and did not activate the complement. Upon incubation with HepG2 cells, ELP-Rapa revealed significant cellular uptake and trafficking to acidic organelles, consistent with lysosomes. Internalized ELP-Rapa nanoparticles increased oxidative stress 4-fold compared to free drug or free ELP controls. However, mice bearing orthotopic hormone receptor positive BT-474 breast tumors, given a high dose (∼10-fold above therapeutic dose) of 1 month administration of ELP-Rapa, did not induce hepatotoxicity. On the other hand, tumor growth and mTOR signaling were suppressed without affecting body weight. Nanoparticles assembled using ELP technology appear to be a safe and efficient strategy for delivering Rapa.
Elucidation of the mTOR pathway and therapeutic applications in dermatology
2016, Actas Dermo-Sifiliograficas
The member of the phosphatidylinositol 3-kinase family, mammalian target of rapamycin, is involved in modulating inflammatory response and regulating cellular processes associated with growth, differentiation, and angiogenesis. Recent years have seen major advances in our understanding of the mammalian target of rapamycin signaling pathway and the implication of this pathway in multiple genetic and inflammatory diseases and tumors. The development of the mammalian target of rapamycin inhibitors has given rise to new treatment approaches that have led to substantially improved outcomes in many diseases. In this article, we review the role of the mammalian target of rapamycin signaling pathway in the different skin diseases with which it has been associated, examine the therapeutic applications of drugs targeting this pathway, and provide an overview of current trends and future directions in research.
La molécula diana de la rapamicina en mamíferos es una cinasa perteneciente a la familia de fosfatidil-3-inositol que está involucrada en la regulación de diferentes procesos relacionados con el crecimiento y diferenciación celular, la angiogénesis y la modulación de la respuesta inflamatoria. En los últimos años hemos presenciado un profundo avance en el conocimiento de las bases moleculares de la vía de señalización de la molécula diana de la rapamicina en mamíferos y su implicación en multitud de enfermedades genéticas, inflamatorias o tumorales. El desarrollo de moléculas inhibidoras de esta vía ha propiciado una nueva posibilidad de abordaje terapéutico que ha permitido una mejora sustancial en muchas de estas enfermedades. En este artículo revisamos las implicaciones de la vía de la molécula diana de la rapamicina en mamíferos en las diferentes dermatosis con las que se ha relacionado, sus aplicaciones farmacológicas y las futuras direcciones que están tomando las diferentes líneas de investigación.
MTOR inhibitors
2015, Actualites Pharmaceutiques
Indiqués en cancérologie et dans la prévention des rejets de greffe, les inhibiteurs de mTOR constituent une famille réduite de molécules au mécanisme d’action pharmacologique complexe et original. Malgré une iatrogénie importante, ces médicaments représentent une famille de molécules prometteuse dans la prise en charge des formes métastasées de cancer.
Indicated in oncology and in the prevention of transplant rejections, mTOR inhibitors are a small family of molecules with a complex and original pharmacological action mechanism. Despite significant adverse effects, these drugs represent a promising family of molecules in the treatment of metastatic forms of cancer.
Everolimus-induced hematologic changes in patients with metastatic breast cancer
2015, Clinical Breast Cancer
Everolimus, which inhibits the mammalian target of rapamycin (mTOR), is increasingly used in breast cancer and familiarity with its full range of toxicity is critical for practicing oncologists.
We studied hematologic changes in 31 patients with metastatic breast cancer treated in a phase II clinical trial using everolimus. Complete blood counts were collected at baseline, 2 weeks, 4 weeks, every 4 weeks during treatment, and 1 month after discontinuation. Adverse events were defined using Common Toxicity Criteria version 3. Linear mixed models with fixed effects of time and random intercepts and slopes were used to study trends and comparisons were conducted using paired t tests.
Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). These were predominantly grade 1 or 2 and did not require dose modification. Red blood cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) both decreased significantly over time (P < .0001) starting at 2 weeks with no significant change in mean corpuscular hemoglobin concentration (MCHC) (P = .104). Both MCV and MCH increased 1 month after treatment discontinuation (P values < .0001 and .0003, respectively) indicating reversibility of this effect. Although total leukocyte counts remained largely stable, lymphocyte percentage progressively decreased over time with a trend for increased neutrophils.
In addition to anemia, leukopenia, and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. Familiarity with these hematologic changes is prudent as more patients are treated with this class of drugs.

View all citing articles on Scopus

^e: These authors contributed equally to this manuscript.

View full text

The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus: A systematic review of the literature and meta-analysis

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Data source

Search results

Discussion

Conclusion

Conflict of interest statement

Acknowledgement

Cancer Cell

Oral Oncol

Leuk Res

J Thorac Oncol

Clin Genitourin Cancer

Current and future directions in mammalian target of rapamycin inhibitors development

Expert Opin Investig Drugs

The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy

Clin Cancer Res

Common toxicities of mammalian target of rapamycin inhibitors

Target Oncol