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Shawer R, Solomon A. Adverse effects of anti-cancer biologics on the ocular surface. Curr Opin Allergy Clin Immunol 2024; 24:390-396. [PMID: 38963724 DOI: 10.1097/aci.0000000000001007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
PURPOSE OF REVIEW Cancer immunotherapy is one of the most emerging and rapidly growing fields.Ocular side effects associated with these therapies are common and can be present in up to 70% of patients.The cornea may be involved in different pathogenic mechanisms triggered by different immunotherapeutic agents, and corneal disease varies from mild symptoms to severe corneal ulceration and melting with visual loss.We aimed to review the incidence, mechanism, and management of ocular surface side effects in cancer patients receiving immunotherapy. RECENT FINDINGS With the recent use of immunotherapeutic agents in cancer patients, in particular immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor (EGFR) inhibitors, ocular surface and corneal involvement are common side effects.These patients can be at risk of sight threatening complications that warrant prompt diagnosis and careful monitoring and management. SUMMARY Immunotherapy- related corneal complications in cancer patients are associated with a decreased quality of life. Prompt recognition and an interdisciplinary approach between ophthalmologists and oncologists are crucial to handle immune related ocular adverse events in these patients, in order to maintain ocular surface integrity and avoid a vision threatening complication.
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Affiliation(s)
- Riham Shawer
- Department of Ophthalmology, Hadassah-Hebrew University Medical Centre
- St. John Eye Hospital, Jerusalem, Israel
| | - Abraham Solomon
- Department of Ophthalmology, Hadassah-Hebrew University Medical Centre
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Bierbrier R, D’Aguanno K, Oliel S, Zeng Y, Esfahani K, Pehr K. An Analysis of Risk Factors for the Development of Acneiform Eruptions in Patients on Monoclonal Antibody Epidermal Growth Factor Receptor Inhibitors. J Cutan Med Surg 2023; 27:614-620. [PMID: 37942582 PMCID: PMC10714707 DOI: 10.1177/12034754231211326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/17/2023] [Indexed: 11/10/2023]
Abstract
Acneiform eruptions occur frequently and early in patients on epidermal growth factor receptor inhibitors (EGFRi). Identification of baseline patient risk factors would prompt earlier referral to dermatology to optimize prevention and management. The primary objective of this retrospective study is to determine the association between clinical and demographic characteristics and the development of acneiform eruptions. A retrospective chart review was conducted on patients diagnosed with colon and head and neck cancers who started EGFRi between January 2017 and December 2021. Patients were followed until death or September 2022. Baseline demographic and clinical parameters were documented and patients were followed from the time of diagnosis to most recent visit for the development and management of an acneiform eruption. Regression analyses were performed to determine the association between baseline characteristics and the development of acneiform eruptions. A total of 66 patients were treated with cetuximab or panitumumab between 2017-2021 were included in the analysis. Forty-seven of the sixty-six patients developed an acneiform eruption while on EGFRi therapy (71.2%). Combination cancer therapy with another chemotherapeutic agent was associated with a lower risk of acneiform eruption (OR 0.03, P = .027). No other baseline features were statistically associated with a lower risk of acneiform eruption. Acneiform eruptions are a common cutaneous adverse event of EGFRi therapy. Ongoing research is required to elucidate risk factors for the development of acneiform eruptions, to improve the quality of life of oncology patients.
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Affiliation(s)
- Rachel Bierbrier
- Division of Dermatology, McGill University, Montreal, QC, Canada
| | | | - Sarah Oliel
- Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Yixiao Zeng
- Quantitative Life Sciences Program, Interfaculty Studies, McGill University, Montréal, Qc, Canada
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
| | - Khashayar Esfahani
- St Mary’s Hospital, McGill University, Montreal, QC, Canada
- Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Kevin Pehr
- Division of Dermatology, McGill University, Montreal, QC, Canada
- Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, QC, Canada
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Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates. Pharmaceutics 2022; 14:pharmaceutics14091917. [PMID: 36145664 PMCID: PMC9505583 DOI: 10.3390/pharmaceutics14091917] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/29/2022] [Accepted: 09/03/2022] [Indexed: 11/18/2022] Open
Abstract
Matuzumab and nimotuzumab are anti-EGFR monoclonal antibodies that bind to different epitopes of domain III of EGFR. We developed 89Zr-matuzumab as a PET probe for diagnosis/monitoring of response to treatment of a noncompeting anti-EGFR nimotuzumab antibody drug conjugate (ADC) using mouse colorectal cancer (CRC) xenografts. We developed 89Zr-matuzumab and performed quality control in EGFR-positive DLD-1 cells. The KD of matuzumab, DFO-matuzumab and 89Zr-matuzumab in DLD-1 cells was 5.9, 6.2 and 3 nM, respectively. A competitive radioligand binding assay showed that 89Zr-matuzumab and nimotuzumab bound to noncompeting epitopes of EGFR. MicroPET/CT imaging and biodistribution of 89Zr-matuzumab in mice bearing EGFR-positive xenografts (HT29, DLD-1 and MDA-MB-231) showed high uptake that was blocked with pre-dosing with matuzumab but not with the noncompeting binder nimotuzumab. We evaluated nimotuzumab-PEG6-DM1 ADC in CRC cells. IC50 of nimotuzumab-PEG6-DM1 in SNU-C2B, DLD-1 and SW620 cells was dependent on EGFR density and was up to five-fold lower than that of naked nimotuzumab. Mice bearing the SNU-C2B xenograft were treated using three 15 mg/kg doses of nimotuzumab-PEG6-DM1, and 89Zr-matuzumab microPET/CT was used to monitor the response to treatment. Treatment resulted in complete remission of the SNU-C2B tumor in 2/3 mice. Matuzumab and nimotuzumab are noncompeting and can be used simultaneously.
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Mihai MM, Ion A, Giurcăneanu C, Nițipir C, Popa AM, Chifiriuc MC, Popa MI, Říčař J, Popa LG, Sârbu I, Lazăr V. The Impact of Long-Term Antibiotic Therapy of Cutaneous Adverse Reactions to EGFR Inhibitors in Colorectal Cancer Patients. J Clin Med 2021; 10:jcm10153219. [PMID: 34362003 PMCID: PMC8347035 DOI: 10.3390/jcm10153219] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is an important public health issue, in terms of incidence and mortality, with approximately 1.8 million new cases reported worldwide in 2018. Advancements in understanding pathophysiological key steps in CRC tumorigenesis have led to the development of new targeted therapies such as those based on epidermal growth factor receptor inhibitors (EGFR inhibitors). The cutaneous adverse reactions induced by EGFR inhibitors, particularly papulopustular rash, often require long-term antibiotic treatment with tetracycline agents (mostly minocycline and doxycycline). However, this raises several issues of concern: possible occurrence of gut dysbiosis in already vulnerable CRC patients, selection of highly antibiotic resistant and/or virulent clones, development of adverse reactions related to tetracyclines, interference of antibiotics with the response to oncologic therapy, with a negative impact on disease prognosis etc. In the context of scarce information regarding these issues and controversial opinions regarding the role of tetracyclines in patients under EGFR inhibitors, our aim was to perform a thorough literature review and discuss the main challenges raised by long-term use of tetracyclines in advanced CRC patients receiving this targeted therapy.
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Affiliation(s)
- Mara Mădălina Mihai
- Department of Oncologic Dermatology, ‘Elias’ Emergency University Hospital, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.G.); (L.G.P.)
- Department of Dermatology, ‘Elias’ Emergency University Hospital, 011461 Bucharest, Romania
- Department of Microbiology, Faculty of Biology, ICUB—Research Institute of the University of Bucharest, 050657 Bucharest, Romania; (M.-C.C.); (V.L.)
- Correspondence: (M.M.M.); (A.I.); Tel.: +40-74-336-4164 (M.M.M.)
| | - Ana Ion
- Department of Dermatology, ‘Elias’ Emergency University Hospital, 011461 Bucharest, Romania
- Correspondence: (M.M.M.); (A.I.); Tel.: +40-74-336-4164 (M.M.M.)
| | - Călin Giurcăneanu
- Department of Oncologic Dermatology, ‘Elias’ Emergency University Hospital, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.G.); (L.G.P.)
- Department of Dermatology, ‘Elias’ Emergency University Hospital, 011461 Bucharest, Romania
| | - Cornelia Nițipir
- Department of Oncology, ‘Elias’ Emergency University Hospital, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.N.); (A.-M.P.)
| | - Ana-Maria Popa
- Department of Oncology, ‘Elias’ Emergency University Hospital, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.N.); (A.-M.P.)
| | - Mariana-Carmen Chifiriuc
- Department of Microbiology, Faculty of Biology, ICUB—Research Institute of the University of Bucharest, 050657 Bucharest, Romania; (M.-C.C.); (V.L.)
| | - Mircea Ioan Popa
- Department of Microbiology, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Jan Říčař
- Department of Dermatology and Venereology, Charles University, Medical School and Teaching Hospital Pilsen, 30599 Pilsen, Czech Republic;
| | - Liliana Gabriela Popa
- Department of Oncologic Dermatology, ‘Elias’ Emergency University Hospital, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.G.); (L.G.P.)
- Department of Dermatology, ‘Elias’ Emergency University Hospital, 011461 Bucharest, Romania
| | - Ionela Sârbu
- Department of Genetics, Faculty of Biology, ICUB—Research Institute of the University of Bucharest, 050657 Bucharest, Romania;
| | - Veronica Lazăr
- Department of Microbiology, Faculty of Biology, ICUB—Research Institute of the University of Bucharest, 050657 Bucharest, Romania; (M.-C.C.); (V.L.)
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Nimotuzumab Site-Specifically Labeled with 89Zr and 225Ac Using SpyTag/SpyCatcher for PET Imaging and Alpha Particle Radioimmunotherapy of Epidermal Growth Factor Receptor Positive Cancers. Cancers (Basel) 2020; 12:cancers12113449. [PMID: 33233524 PMCID: PMC7699480 DOI: 10.3390/cancers12113449] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Monoclonal antibodies (IgG) are excellent probes for targeting cell surface receptors for imaging and therapeutic applications. These theranostic agents are often developed by randomly conjugating radioisotopes/drugs/chelators to the primary amine of lysine or the sulfhydryl groups of cysteine on the antibody. Random conjugation often alters the properties of the antibody. We have site-specifically radiolabeled nimotuzumab an anti-epidermal growth factor receptor (EGFR) monoclonal antibody with 89Zr and 225Ac using SpyTag: ∆N-SpyCatcher for positron emission tomography (PET) imaging and alpha particle radiotherapy, and evaluated these agents in a model of EGFR-positive triple negative breast cancer (TNBC). Nimotuzumab-SpyTag-∆N-SpyCatcher constructs showed improved binding in vitro compared with randomly conjugated constructs. 89Zr-nimotuzumab-SpyTag-∆N-SpyCatcher specifically delineated EGFR-positive xenograft in vivo using microPET/CT imaging. Compared with control treatment groups, 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher more than doubled the survival of mice bearing EGFR-positive MDA-MB-231 TNBC xenograft. This work highlights a facile method to site-specifically radiolabel antibodies using SpyTag: ∆N-SpyCatcher. Abstract To develop imaging and therapeutic agents, antibodies are often conjugated randomly to a chelator/radioisotope or drug using a primary amine (NH2) of lysine or sulfhydryl (SH) of cysteine. Random conjugation to NH2 or SH groups can require extreme conditions and may affect target recognition/binding and must therefore be tested. In the present study, nimotuzumab was site-specifically labeled using ∆N-SpyCatcher/SpyTag with different chelators and radiometals. Nimotuzumab is a well-tolerated anti-EGFR antibody with low skin toxicities. First, ΔN-SpyCatcher was reduced using tris(2-carboxyethyl)phosphine (TCEP), which was followed by desferoxamine-maleimide (DFO-mal) conjugation to yield a reactive ΔN-SpyCatcher-DFO. The ΔN-SpyCatcher-DFO was reacted with nimotuzumab-SpyTag to obtain stable nimotuzumab-SpyTag-∆N-SpyCatcher-DFO. Radiolabeling was performed with 89Zr, and the conjugate was used for the in vivo microPET imaging of EGFR-positive MDA-MB-468 xenografts. Similarly, ∆N-SpyCatcher was conjugated to an eighteen-membered macrocyclic chelator macropa-maleimide and used to radiolabel nimotuzumab-SpyTag with actinium-225 (225Ac) for in vivo radiotherapy studies. All constructs were characterized using biolayer interferometry, flow cytometry, radioligand binding assays, HPLC, and bioanalyzer. MicroPET/CT imaging showed a good tumor uptake of 89Zr-nimotuzumab-SpyTag-∆N-SpyCatcher with 6.0 ± 0.6%IA/cc (n = 3) at 48 h post injection. The EC50 of 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher and 225Ac-control-IgG-SpyTag-∆N-SpyCatcher against an EGFR-positive cell-line (MDA-MB-468) was 3.7 ± 3.3 Bq/mL (0.04 ± 0.03 nM) and 18.5 ± 4.4 Bq/mL (0.2 ± 0.04 nM), respectively. In mice bearing MDA-MB-468 EGFR-positive xenografts, 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher significantly (p = 0.0017) prolonged the survival of mice (64 days) compared to 225Ac-control IgG (28.5 days), nimotuzumab (28.5 days), or PBS-treated mice (30 days). The results showed that the conjugation and labeling using SpyTag/∆N-SpyCatcher to nimotuzumab did not significantly (p > 0.05) alter the receptor binding of nimotuzumab compared with a non-specific conjugation approach. 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher was effective in vitro and in an EGFR-positive triple negative breast cancer xenograft model.
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Wong SF, Unger JM, Wade JL, Wagner LI, Lacouture ME, Humphries KC, Moseley A, Arnold K, Velasco MR, Floyd JD, Esparaz BT, Barzi A, Lenz HJ, Koczywas M, Dakhil S, Burton GV, Fisch MJ, Henry NL, Hershman DL, Moinpour CM. A prospective study to validate the functional assessment of cancer therapy (FACT) for epidermal growth factor receptor inhibitor (EGFRI)-induced dermatologic toxicities FACT-EGFRI 18 questionnaire: SWOG S1013. J Patient Rep Outcomes 2020; 4:54. [PMID: 32642992 PMCID: PMC7343679 DOI: 10.1186/s41687-020-00220-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 06/18/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Papulopustular rash is a common class effect of epidermal growth factor receptor inhibitors (EGFRI) that can affect patients' health-related quality of life and cause disruptions to treatment. SWOG S1013 (NCT01416688) is a multi-center study designed to validate the Functional Assessment of Cancer Therapy EGFRI 18 (FACT-EGFRI 18) using 7-items from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 to assess EGFRI-induced skin-related toxicities and their impact on functional status. METHODS Patients with a diagnosis of colorectal or lung cancer to receive EGFRI therapies for at least 6 weeks were enrolled. Patient self-assessments using the FACT-EGFRI 18 were completed prior to undergoing CTCAE assessment by trained clinicians at baseline, weekly × 6, and then monthly × 3. The psychometric properties of the FACT-EGFRI 14 (skin toxicity items only) and 18 (plus 2 nail and 2 hair items) were established based on criterion validity, known groups validity, internal consistency reliability, and responsiveness to change. RESULTS Of the 146 registered patients, 124 were evaluable. High Cronbach's alpha (> 0.70) for both FACT-EGFRI 14 and FACT-EGFRI 18 scores across assessment times were observed. Although agreement (i.e. criterion validity) between individual and summary scales of the FACT-EGFRI 18 for assessing skin toxicity was good, agreement with the clinician-reported CTCAE was only fair. The minimal important difference was determined to be 3 points. The results also demonstrated responsiveness to symptom change. DISCUSSION Based on the results of this multi-center validation study, the FACT-EGFRI 18 patient-reported outcome instrument provided data from the patient's perspective yielding unique information as well as complementing clinician-rated CTCAE grades, especially for the symptoms of pain, pruritus, and paronychia. CONCLUSIONS Good to excellent psychometric properties for the FACT-EGFRI 18 were demonstrated, supporting further use of this patient-reported outcomes measure. Additional validation with a more diverse group of patients should be conducted.
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Affiliation(s)
- Siu-Fun Wong
- Chapman University School of Pharmacy, Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, CA, USA.
| | - Joseph M Unger
- SWOG Statistics and Data Management Center/Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - James L Wade
- Heartland Cancer Research NCORP/Cancer Care Specialists of Central Illinois, Decatur, IL, USA
| | | | | | - Keisha C Humphries
- Heartland Cancer Research NCORP/Cancer Care Specialists of Central Illinois, Decatur, IL, USA
| | - Anna Moseley
- SWOG Statistics and Data Management Center/Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Kathryn Arnold
- SWOG Statistics and Data Management Center/Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Mario R Velasco
- Heartland Cancer Research NCORP/Cancer Care Specialists of Central Illinois, Decatur, IL, USA
| | - Justin D Floyd
- Wichita NCORP, Wichita, KS, USA.,Heartland Cancer Research NCORP/Cancer Care Specialists of Central Illinois, Swansea, IL, USA
| | - Benjamin T Esparaz
- Heartland Cancer Research NCORP/Cancer Care Specialists of Central Illinois, Decatur, IL, USA
| | - Afsaneh Barzi
- University of Southern California, Los Angeles, CA, USA
| | | | | | - Shaker Dakhil
- Wichita NCORP/ Cancer Center of Kansas, Wichita, Wichita, KS, USA
| | - Gary V Burton
- Gulf South MU NCORP/Louisiana State University HSC-Shreveport, Shreveport, LA, USA
| | | | - N Lynn Henry
- University of Michigan Medical School, Ann Arbor, MI, USA
| | | | - Carol M Moinpour
- Fred Hutchinson Cancer Research Center, Public Health Sciences Division (Emerita), Seattle, WA, USA
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Bouché O, Ben Abdelghani M, Labourey JL, Triby S, Bensadoun RJ, Jouary T, Des Guetz G. Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer. World J Gastroenterol 2019; 25:4007-4018. [PMID: 31413534 PMCID: PMC6689814 DOI: 10.3748/wjg.v25.i29.4007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/07/2019] [Accepted: 02/23/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown.
AIM To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management.
METHODS Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up.
RESULTS Overall, 229 patients (males, 57.6%; mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity; the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%; emollients, 75.5%; both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low.
CONCLUSION The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient’s quality of life appeared to be limited.
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Affiliation(s)
- Olivier Bouché
- Department of Gastroenterology and Digestive Oncology, Hôpital Robert Debré, CHU Reims, Reims 51000, France
| | | | | | - Simon Triby
- Medical Department, AMGEN France, Boulogne-Billancourt 92100, France
| | | | - Thomas Jouary
- Dermatology Department, Hôpital Saint-André, CHU de Bordeaux, Bordeaux 33000, France
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Muratori L, La Salvia A, Gorzegno G, Sperone P, Scagliotti GV. Long-term disease control in a metastatic squamous cell carcinoma of the oral cavity treated with maintenance metronomic capecitabine. J Oncol Pharm Pract 2019; 26:240-243. [PMID: 31042137 DOI: 10.1177/1078155219845433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Recurrent or metastatic disease occurs in two-thirds of head and neck squamous cell carcinomas and it is associated with poor prognosis. Systemic treatment with platinum-based chemotherapy in combination with the epidermal growth factor receptor-targeting monoclonal antibody cetuximab represents a preferred option for these patients. Upon the achievement of tumor response by combined treatment, maintenance with single-agent cetuximab is usually administered with the aim of prolonging disease control at the price of reasonable toxicity. Although rarely, however, cetuximab needs to be discontinued in the absence of disease progression because of intolerable side effects. Here we describe the case of a 66-year-old man with a metastatic cancer of oral cavity, who had to discontinue maintenance cetuximab and who achieved prolonged disease control with metronomic capecitabine. We suggest that capecitabine could be an effective and safe maintenance option in case of cetuximab intolerance.
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Affiliation(s)
- Leonardo Muratori
- Medical Oncology, Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Turin, Italy
| | - Anna La Salvia
- Medical Oncology, Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Turin, Italy
| | - Gabriella Gorzegno
- Medical Oncology, Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Turin, Italy
| | - Paola Sperone
- Medical Oncology, Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Turin, Italy
| | - Giorgio V Scagliotti
- Medical Oncology, Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Turin, Italy
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Hartimath SV, El-Sayed A, Makhlouf A, Bernhard W, Gonzalez C, Hill W, Parada AC, Barreto K, Geyer CR, Fonge H. Therapeutic potential of nimotuzumab PEGylated-maytansine antibody drug conjugates against EGFR positive xenograft. Oncotarget 2019; 10:1031-1044. [PMID: 30800216 PMCID: PMC6383682 DOI: 10.18632/oncotarget.26613] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 12/20/2018] [Indexed: 12/26/2022] Open
Abstract
Nimotuzumab is a humanized anti-epidermal growth factor receptor I (EGFR) monoclonal antibody. We have developed antibody drug conjugates (ADCs) with nimotuzumab conjugated to PEGylated-maytansine (PEG6-DM1). We generated conjugates with low (nimotuzumab-PEG6-DM1-Low: DAR = 3.5) and high (nimotuzumab-PEG6-DM1-High: DAR = 7.3) drug to antibody ratios (DAR). Quality control was performed using UV spectrophotometry, size exclusion HPLC, bioanalyzer, biolayer interferometry (BLI), and flow cytometry in EGFR-positive DLD-1, MDA-MB-468 (high density EGFR), and HT-29 (very low EGFR density) cells. Control antibody drug conjugates were developed using a human anti-maltose binding protein (MBP) antibody. BLI showed that the binding of nimotuzumab-PEG6-DM1-Low and nimotuzumab-PEG6-DM1-High was slightly but significantly affected by conjugation of the drug (nimotuzumab KD 0.89 ± 0.02 nM < nimotuzumab-PEG6-DM1-Low KD 1.94 ± 0.02 nM < nimotuzumab-PEG6-DM1-High KD 3.75 ± 0.03 nM). In vitro cytotoxicity was determined following incubation of cells with the immunoconjugates and IC50 values were determined. Nimotuzumab-PEG6-DM1-Low and nimotuzumab-PEG6-DM1-High were used to treat EGFR positive KRAS mutant DLD-1 colorectal cancer xenograft. DLD-1 cells were transduced with a red fluorescent protein (iRFP702) to allow the use of near infrared imaging (NIR) for tumor response monitoring. In vitro potency correlated with the number of drugs on antibody, with nimotuzumab-PEG6-DM1-High showing higher activity than nimotuzumab-PEG6-DM1-Low. Three doses (15 mg/kg) of the ADCs prolonged the survival of DLD-1-iRFP-702 tumor bearing mice as monitored by NIR. Nimotuzumab-PEG6-DM1-Low resulted in 4/6 complete cure while nimotuzumab-PEG6-DM1-High resulted in 2/5 complete cure. The novel ADCs were very effective in a colorectal cancer model in vivo.
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Affiliation(s)
- Siddesh V Hartimath
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 0W8, Canada.,Saskatchewan Centre for Cyclotron Sciences (SCCS), the Fedoruk Centre, Saskatoon SK, S7N 5C4, Canada
| | - Ayman El-Sayed
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 5E5, Canada
| | - Amal Makhlouf
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 0W8, Canada.,Saskatchewan Centre for Cyclotron Sciences (SCCS), the Fedoruk Centre, Saskatoon SK, S7N 5C4, Canada.,Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini, 12411, Cairo, Egypt
| | - Wendy Bernhard
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 5E5, Canada
| | - Carolina Gonzalez
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 5E5, Canada
| | - Wayne Hill
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 5E5, Canada
| | | | - Kris Barreto
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 5E5, Canada
| | - Clarence Ronald Geyer
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 5E5, Canada
| | - Humphrey Fonge
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon SK, S7N 0W8, Canada.,Saskatchewan Centre for Cyclotron Sciences (SCCS), the Fedoruk Centre, Saskatoon SK, S7N 5C4, Canada.,Department of Medical Imaging, Royal University Hospital Saskatoon, Saskatoon SK, S7N 0W8, Canada
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Hartimath SV, Alizadeh E, Solomon VR, Chekol R, Bernhard W, Hill W, Parada AC, Barreto K, Geyer CR, Fonge H. Preclinical Evaluation of 111In-Labeled PEGylated Maytansine Nimotuzumab Drug Conjugates in EGFR-Positive Cancer Models. J Nucl Med 2019; 60:1103-1110. [PMID: 30655327 DOI: 10.2967/jnumed.118.220095] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022] Open
Abstract
Epidermal growth factor receptor I (EGFR) is overexpressed in most cancers of epithelial origin. Antibody drug conjugates (ADCs) with PEGylated-maytansine (PEG-DM1) show promise in vitro and in vivo. However, in vivo biodistribution data for ADCs with PEG-DM1 have not been reported. Development of methods to understand the real-time in vivo behavior of these ADCs is needed to move these compounds to the clinic. Methods: Here we have used noninvasive small-animal SPECT/CT imaging and ex vivo biodistribution to understand the in vivo behavior of PEG6-DM1 ADCs. We developed nimotuzumab ADCs conjugated to PEG6-DM1. We generated immunoconjugates with low (nimotuzumab-PEG6-DM1-Low) and high (nimotuzumab-PEG6-DM1-High) drug-to-antibody ratios. The drug-to-antibody of nimotuzumab-PEG6-DM1-Low and nimotuzumab-PEG6-DM1-High was 3.5 and 7.3, respectively. Quality control was performed using ultraviolet spectrophotometry, size-exclusion high-performance liquid chromatography, bioanalyzer, biolayer interferometry, and flow cytometry in EGFR-positive DLD-1 cells. These immunoconjugates were conjugated with DOTA and radiolabeled with 111In. The in vitro binding and internalization rates of 111In-nimotuzumab, 111In-nimotuzumab-PEG6-DM1-Low, and 111In-nimotuzumab-PEG6-DM1-High were characterized. Furthermore, the pharmacokinetics, biodistribution, and imaging characteristics were evaluated in normal and DLD-1 tumor-bearing mice. Results: Flow cytometry and biolayer interferometry showed a trend toward decreasing EGFR affinity with increasing number of PEG6-DM1 on the antibody. Despite the lower overall cellular binding of the PEG6-DM1 radioimmunoconjugates, internalization was higher for PEG6-DM1 ADCs than for the non-PEGylated ADC in the following order: 111In-nimotuzumab-PEG6-DM1-High > 111In-nimotuzumab-PEG6-DM1-Low > 111In-nimotuzumab. Nuclear uptake of 111In-nimotuzumab-PEG6-DM1-High was 4.4-fold higher than 111In-nimotuzumab. Pharmacokinetics and biodistribution showed that 111In-nimotuzumab-PEG6-DM1-High had the slowest blood and whole-body clearance rate. Uptake in DLD-1 tumors of 111In-nimotuzumab was similar to 111In-nimotuzumab-PEG6-DM1-Low but was significantly higher than for 111In-nimotuzumab-PEG6-DM1-High. Tumor-to-background ratios for 111In-nimotuzumab and 111In-nimotuzumab-PEG6-DM1-Low were higher than for 111In-nimotuzumab-PEG6-DM1-High. Conclusion: The results show that conjugation of multiple PEG6-DM1 reduces the affinity for EGFR in vitro. However, the reduced affinity is counteracted by the high internalization rate of constructs with PEG6-DM1 ADCs in vitro. The decreased affinity resulted in low tumor uptake of 111In-nimotuzumab-PEG6-DM1-High, with a slow overall whole-body clearance rate. These data provide insights for evaluating the pharmacokinetics and normal -tissue toxicity and in determining dosing rate of PEGylated ADCs.
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Affiliation(s)
- Siddesh V Hartimath
- Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada
| | - Elahe Alizadeh
- Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada
| | - Viswas Raja Solomon
- Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada
| | - Rufael Chekol
- Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada
| | - Wendy Bernhard
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada
| | - Wayne Hill
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada
| | | | - Kris Barreto
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada
| | - Clarence Ronald Geyer
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada
| | - Humphrey Fonge
- Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon SK, Canada .,Department of Medical Imaging, Royal University Hospital (RUH), Saskatoon SK, Canada
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11
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12
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Im JS, Herrmann AC, Bernatchez C, Haymaker C, Molldrem JJ, Hong WK, Perez-Soler R. Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer. PLoS One 2016; 11:e0160004. [PMID: 27467256 PMCID: PMC4965069 DOI: 10.1371/journal.pone.0160004] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 07/12/2016] [Indexed: 11/18/2022] Open
Abstract
Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation.
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Affiliation(s)
- Jin S. Im
- Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
- * E-mail:
| | - Amanda C. Herrmann
- Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Chantale Bernatchez
- Department of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Cara Haymaker
- Department of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Jeffrey J. Molldrem
- Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Waun Ki Hong
- Department of Thoracic H&N Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Roman Perez-Soler
- Division of Oncology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
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13
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Charles C, Bungener C, Razavi D, Mateus C, Routier E, Lanoy E, Verschoore M, Robert C, Dauchy S. Impact of dermatologic adverse events induced by targeted therapies on quality of life. Crit Rev Oncol Hematol 2016; 101:158-68. [PMID: 26995080 DOI: 10.1016/j.critrevonc.2016.03.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 01/16/2016] [Accepted: 03/02/2016] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Investigations about the impact of dermatologic adverse events on quality of life in the context of targeted therapies are quite recent and results vary in some dimensions. This article aims to summarize the existing data and to clarify needs in terms of clinical management and future research. METHODS A literature review was done with Pubmed, Medline, Scopus and PsycInfo databases and it combined the empirical studies published in English and in French over the past ten years. RESULTS AND CONCLUSIONS Dermatologic adverse events globally have a low to moderate impact on quality of life, mainly in the physical and emotional domains. Reasons for inter-individual variations in adjustment and long-term impact are still not well known. Making quality of life assessments systematic, making early referrals of patients to dermatology consultations and giving more attention to individual experience were identified as measures that could help prevent deterioration in quality of life.
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Affiliation(s)
- Cécile Charles
- Psycho-Oncology Unit, Gustave Roussy, Villejuif, France; Laboratory of Psychopathology and Health Processes, EA 4057, Psychology Institute, Paris Descartes University-Sorbonne Paris Cité, Boulogne-Billancourt, France.
| | - Catherine Bungener
- Laboratory of Psychopathology and Health Processes, EA 4057, Psychology Institute, Paris Descartes University-Sorbonne Paris Cité, Boulogne-Billancourt, France
| | - Darius Razavi
- Psychosomatic and Psycho-Oncology Research Unit, University of Brussels-Psycho-Oncology Clinic, Jules Bordet Institute, Brussels, Belgium
| | - Christine Mateus
- Dermatology Service, Gustave Roussy Cancer Campus Grand-Paris-Sud, Villejuif, France
| | - Emilie Routier
- Dermatology Service, Gustave Roussy Cancer Campus Grand-Paris-Sud, Villejuif, France
| | - Emilie Lanoy
- Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France
| | | | - Caroline Robert
- Dermatology Service, Gustave Roussy Cancer Campus Grand-Paris-Sud, Villejuif, France
| | - Sarah Dauchy
- Psycho-Oncology Unit, Gustave Roussy, Villejuif, France
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14
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Boers-Doets C, Lacouture M, Langenhoff J, van Zuuren EJ, Stijnen T, Brakenhoff J, Ouwerkerk J, Galimont A, Bro W, Nortier H. Interventions for skin reactions associated with targeted anticancer treatments. Hippokratia 2015. [DOI: 10.1002/14651858.cd009236.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
| | - Mario Lacouture
- Memorial Sloan Kettering Cancer Center; Department of Medicine, Dermatology Service; 160 East 53rd St New York USA 10022
| | - Jessica Langenhoff
- Leiden University Medical Center; Walaeus Library; PO Box 9600 Leiden Netherlands 2300 RC
| | - Esther J van Zuuren
- Leiden University Medical Center; Department of Dermatology; PO Box 9600 B1-Q Leiden Netherlands 2300 RC
| | - Theo Stijnen
- Leiden University Medical Center; Department of Medical Statistics; PO Box 9600 Leiden Netherlands 2300 RC
| | - Jan Brakenhoff
- Waterland Hospital; Department of Internal Medicine; PO-box 250 Purmerend Netherlands 1440 AG
| | - Jan Ouwerkerk
- Leiden University Medical Center; Department of Clinical Oncology; PO Box 9600 Leiden Netherlands 2300 RC
| | - Annemie Galimont
- Admiraal de Ruyter Hospital; Department of Dermatology; 's-Gravenpolderse-weg 114 Goes Netherlands 4462 RA
| | - William Bro
- Kidney Cancer Association; 1234 Sherman Ave Ste 203 Evanston Illinois USA 60202
| | - Hans Nortier
- Leiden University Medical Center; Department of Clinical Oncology; PO Box 9600 Leiden Netherlands 2300 RC
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15
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Paul T, Schumann C, Rüdiger S, Boeck S, Heinemann V, Kächele V, Steffens M, Scholl C, Hichert V, Seufferlein T, Stingl JC. Cytokine regulation by epidermal growth factor receptor inhibitors and epidermal growth factor receptor inhibitor associated skin toxicity in cancer patients. Eur J Cancer 2014; 50:1855-63. [PMID: 24857781 DOI: 10.1016/j.ejca.2014.04.026] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 04/26/2014] [Indexed: 12/15/2022]
Abstract
AIM Epidermal growth factor receptor inhibitor (EGFRI) induced skin toxicity has a prognostic value suggesting skin toxicity can be a useful surrogate marker for successful epidermal growth factor receptor (EGFR) inhibition, improved response and survival. But the pathophysiology of EGFRI induced skin toxicity remains elusive. However the involvement of immunological mechanisms has been speculated. This study investigates the possible underlying mechanism of EGFR inhibition associated cytokine production in keratinocytes as well as in patients after treatment with epidermal growth factor receptor inhibitors (EGFRIs). METHODS Normal human epidermal keratinocytes (NHEK) were incubated for 2 and 24h with different concentrations of EGFRI (erlotinib) for Western blot analysis and cytokine expression analysis, respectively. Inhibition of EGFR, extracellular-signal-regulated kinase 1/2 (Erk 1/2) and c-Jun was examined by Western blot analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the NHEK cell supernatant and also in the serum of 186 cancer patients who are followed up for EGFRI induced skin rash. RESULTS A significant inhibitory effect of EGFRI was seen on EGFR (Y845), Erk 1/2 and c-Jun in a dose dependent manner. Further downstream, increased CC-chemokine ligand 2 (CCL2), CC-chemokine ligand 5 (CCL5) and decreased interleukin-8 (IL-8) or CXCL8 expression was observed in keratinocytes. In EGFRI treated patients, low levels of serum CXCL8 corresponding to stronger EGFR inhibition were associated with a higher grade of skin toxicity (p=0.0016) and a prolonged overall survival (p=0.018). CONCLUSIONS The results obtained in this study indicate that EGFRI can regulate cytokines by modulating EGFR signalling pathway in keratinocytes. Moreover, serum levels of CXCL8 in EGFRI treated patients may be important for individual EGFRI induced skin toxicity and patient's survival.
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Affiliation(s)
- Tanusree Paul
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany
| | | | - Stefan Rüdiger
- Department of Internal Medicine II, University of Ulm, Ulm, Germany
| | - Stefan Boeck
- Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Volker Heinemann
- Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Volker Kächele
- Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - Michael Steffens
- Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany
| | - Catharina Scholl
- Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany
| | - Vivien Hichert
- Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany
| | | | - Julia Carolin Stingl
- Research Division, Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany; Faculty of Medicine, University of Bonn, Bonn, Germany.
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Epidermal growth factor receptor inhibitors: a review of cutaneous adverse events and management. Dermatol Res Pract 2014; 2014:734249. [PMID: 24723942 PMCID: PMC3958662 DOI: 10.1155/2014/734249] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 01/23/2014] [Indexed: 12/14/2022] Open
Abstract
Epidermal growth factor inhibitors (EGFRI), the first targeted cancer therapy, are currently an essential treatment for many advance-stage epithelial cancers. These agents have the superior ability to target cancers cells and better safety profile compared to conventional chemotherapies. However, cutaneous adverse events are common due to the interference of epidermal growth factor receptor (EGFR) signaling in the skin. Cutaneous toxicities lead to poor compliance, drug cessation, and psychosocial discomfort. This paper summarizes the current knowledge concerning the presentation and management of skin toxicity from EGFRI. The common dermatologic adverse events are papulopustules and xerosis. Less common findings are paronychia, regulatory abnormalities of hair growth, maculopapular rash, mucositis, and postinflammatory hyperpigmentation. Radiation enhances EGFRI rash due to synergistic toxicity. There is a positive correlation between the occurrence and severity of cutaneous adverse effects and tumor response. To date, prophylactic systemic tetracycline and tetracycline class antibiotics have proven to be the most effective treatment regime.
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17
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[Cutaneous adverse reactions of EGFR (epidermal growth factor receptor)-inhibitors: therapeutic algorithm of the French PROCUR group]. Bull Cancer 2013; 100:417-26. [PMID: 23694934 DOI: 10.1684/bdc.2013.1735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The epidermal growth factor receptors (EGFR)-inhibitors are frequently responsible for cutaneous adverse drug reactions that may alter the patients' quality of life and hamper the continuation of treatment. We present here the experience of a group of French multidisciplinary experts - the PROCUR group (PRise en charge de la tOxicité CUtanée des anti-EGFR) - created in order to establish a therapeutic algorithm. It was built in three steps under the responsibility of a steering committee: (1) a systematic literature review was performed by a group of three dermatologists and one oncologist; (2) regional meetings evaluated practical aspect of the treatments in France; (3) a final meeting confrontating the practices in France and the evidence-based medicine including the steering committee, the bibliographic group, and oncologists, radiotherapists, dermatologists and hepato-gastroenterologists involved in regional scientific committees, resulted in a therapeutic algorithm, resulting in the collegial writing of this algorithm. This multidisciplinary study should facilitate the standardised, optimised management of skin toxicity associated with EGFR-inhibitors.
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18
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A review of the treatment options for skin rash induced by EGFR-targeted therapies: Evidence from randomized clinical trials and a meta-analysis. Radiol Oncol 2013; 47:166-75. [PMID: 23801914 PMCID: PMC3691090 DOI: 10.2478/raon-2013-0014] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 12/15/2012] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Agents targeting the epidermal growth factor receptor (EGFR) are amongst the most extensively used of the targeted agents in the therapy of some of the most common solid tumors. Although they avoid many of the classic side effects associated with cytotoxic chemotherapy, they are associated with unpleasant cutaneous toxicities which can affect treatment compliance and impinge on patient quality of life. To date, despite a plethora of consensus recommendations, expert opinions and reviews, there is a paucity of evidence-based guidance for the management of the skin rash that occurs in the treatment of patients receiving EGFR-targeted therapies. METHODS A literature search was conducted as a first step towards investigating not only an evidence-based approach to the management of skin rash, but also with a view to designing future randomized trials. RESULTS The literature search identified seven randomized trials and a meta-analysis was conducted using the data from four of these trials involving oral antibiotics. The meta-analysis of the data from these four trials suggests that prophylactic antibiotics might reduce the relative risk of severe rash associated with EGFR-targeted agents by 42-77%. Vitamin K cream was also identified as having a potential role in the management EGFR-targeted agent induced rash. CONCLUSIONS This review and meta-analysis clearly identify the need for further randomized studies of the role of oral antibiotics in this setting. The results of the ongoing randomized trials of the topical application of vitamin K cream plus or minus doxycycline and employing prophylactic versus reactive strategies are eagerly awaited.
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Lee SL, Tan BS, Chan LC. Paronychia induced by the epidermal growth factor receptor inhibitor cetuximab. J Oncol Pharm Pract 2012; 19:273-8. [PMID: 23161875 DOI: 10.1177/1078155212461289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
While the development of epidermal growth factor receptor inhibitors has been hailed as a remarkable triumph in the field of oncology, it has inherited with it a host of cutaneous side-effects that have been increasingly observed in a substantial number of patients in the recent years. One cutaneous manifestation that may inflict significant pain and affect activities of daily living among some of the patients receiving epidermal growth factor receptor inhibitors is paronychia. A case of paronychia associated with the use of cetuximab in the management of KRAS wild-type midrectal adenocarcinoma along with its management has been described.
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Affiliation(s)
- Soo Lin Lee
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Malaysia.
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20
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Bangsgaard N, Houtkamp M, Schuurhuis DH, Parren PWHI, Baadsgaard O, Niessen HWM, Skov L. Neutralization of IL-8 prevents the induction of dermatologic adverse events associated with the inhibition of epidermal growth factor receptor. PLoS One 2012; 7:e39706. [PMID: 22761877 PMCID: PMC3382563 DOI: 10.1371/journal.pone.0039706] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 05/25/2012] [Indexed: 01/25/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) inhibitors are widely used in the treatment of cancer. EGFR-targeted treatment is known to be associated with a high incidence of dermatological adverse reactions, including papulopustular rash, which can be dose-limiting and may affect compliance to treatment. Currently, the pathways involved in EGFR inhibitor-induced rash are poorly understood and few treatment options for this adverse event are available. Here, we developed a model for induction of papulopustular rash in healthy human volunteers by subcutaneous injection of the anti-EGFR monoclonal antibody zalutumumab. The injection sites and surrounding skin were evaluated by a dermatologist for the presence or absence of papulopustular rash and skin biopsies were taken to confirm the macroscopical findings by immunohistochemistry. Locally injected zalutumumab induced a papulopustular rash, characterized by acute follicular neutrophil-rich hair follicle inflammation, and thus mimicked adverse events induced by systemic administration of EGFR inhibitors. In this model, we tested the hypothesis that neutrophils, attracted by IL-8, play a central role in the observed rash. Indeed, concomitant local repeat dose treatment with HuMab-10F8, a neutralizing human antibody against IL-8, reduced the rash. Inhibition of IL-8 can therefore ameliorate dermatological adverse events induced by treatment with EGFR inhibitors.
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Affiliation(s)
- Nannie Bangsgaard
- Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
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21
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Reguiai Z, Bachet JB, Bachmeyer C, Peuvrel L, Beylot-Barry M, Bezier M, Boucher E, Chevelle C, Colin P, Guimbaud R, Mineur L, Richard MA, Artru P, Dufour P, Gornet JM, Samalin E, Bensadoun RJ, Ychou M, André T, Dreno B, Bouché O. Management of cutaneous adverse events induced by anti-EGFR (epidermal growth factor receptor): a French interdisciplinary therapeutic algorithm. Support Care Cancer 2012; 20:1395-404. [PMID: 22539049 DOI: 10.1007/s00520-012-1451-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 03/26/2012] [Indexed: 12/01/2022]
Abstract
PURPOSE Cutaneous adverse events induced by epidermal growth factor receptor (EGFR) inhibitors can hamper the patients' quality of life. The aim of our work was to draft an algorithm for the optimised management of this skin toxicity. METHODS This algorithm was built in three steps under the responsibility of a steering committee. Step I: a systematic literature analysis (SLA) has been performed. Step II: the collection of information about practices was performed through a questionnaire.These questions were asked during regional meetings to which oncologists, gastro-enterologists, radiotherapists, and dermatologists were invited. Step III: a final meeting was organised involving the bibliography group and the steering committee and regional scientific committees for proposing a final algorithm. RESULTS Step I: 14 publications were selected to evaluate the use of cyclines as curative or prophylactic treatment of the folliculitis induced by EGFR inhibitors. Nineteen publications were retained for the topical treatment of the folliculitis. Forty-six articles were selected for the management of the cutaneous lesions in link with appendages and 12 for xerosis and pruritus. Step II: 96 delegates attended the seven regional meetings and 67 questionnaires were analysed. Step III: a final algorithm was proposed on the basis of the conclusions of the first two steps and expert opinions present at this final meeting. The different propositions were unanimously approved by the 14 experts who voted. CONCLUSIONS This multidisciplinary study summarising published data and current practices produced a therapeutic algorithm, which should facilitate the standardised, optimised management of skin toxicity associated with EGFR inhibitors in France.
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Affiliation(s)
- Z Reguiai
- Department of Dermatology, CHU Reims, Hôpital Robert Debré, avenue du Général Koenig, 51092 Reims, France.
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22
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Bachet JB, Peuvrel L, Bachmeyer C, Reguiai Z, Gourraud PA, Bouché O, Ychou M, Bensadoun RJ, Dreno B, André T. Folliculitis induced by EGFR inhibitors, preventive and curative efficacy of tetracyclines in the management and incidence rates according to the type of EGFR inhibitor administered: a systematic literature review. Oncologist 2012; 17:555-68. [PMID: 22426526 DOI: 10.1634/theoncologist.2011-0365] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Folliculitis is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors (EGFRIs). It is often apparent, altering patients' quality of life and possibly impacting compliance. Variations in terms of the treatment-related incidence and intensity have not been fully elucidated. Tetracyclines have been recommended for the prophylaxis and treatment of folliculitis but their efficacy is yet to be established. MATERIALS AND METHODS We carried out two systematic literature reviews. The first assessed the preventive and curative efficacy of tetracyclines. The second assessed the incidence of grade 3-4 folliculitis in the main clinical studies published. RESULTS In four randomized studies, preventive tetracycline treatment was associated with a significantly lower incidence of grade 2-3 folliculitis and a better quality of life in three of the four studies. In curative terms, tetracycline efficacy was not evaluated in any randomized study, but an improvement in grade ≥2 folliculitis was reported in case series. The frequency and severity of folliculitis seem to be greater with the antibodies than with the tyrosine kinase inhibitors. Analysis restricted to lung cancer studies showed a statistically greater incidence in terms of grade 3-4 folliculitis with cetuximab (9%) and erlotinib (8%) than with gefitinib (2%) (p < .0001). CONCLUSION Unless contraindicated, a tetracycline should be routinely prescribed prophylactically for patients treated with an EGFRI (level of evidence, B2). In curative therapy, the level of evidence for tetracycline efficacy is low (level of evidence, D). The incidence of grade 3-4 folliculitis induced by EGFRIs appears to be lower with gefitinib.
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Affiliation(s)
- Jean-Baptiste Bachet
- Department of Hepato-Gastro-Enterology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre & Marie Curie, Paris, France
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Boucher J, Olson L, Piperdi B. Preemptive management of dermatologic toxicities associated with epidermal growth factor receptor inhibitors. Clin J Oncol Nurs 2012; 15:501-8. [PMID: 21951736 DOI: 10.1188/11.cjon.501-508] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Epidermal growth factor receptor inhibitors (EGFRIs) are a treatment option for patients diagnosed with advanced-stage gastrointestinal, lung, and head and neck cancers. The most prevalent complications associated with EGFRIs are dermatologic toxicities, which may result in either disruption or discontinuation of treatment and adversely affect patients' quality of life. Nurses play a vital role in educating patients about EGFRI-related dermatologic toxicities; therefore, nurses must continue to educate themselves on the various aspects of EGFRI treatment. An overview of the EGF signaling pathway is provided, and dermatologic toxicities associated with EGFRI treatment are described. A review of several studies evaluating reactive skin treatment regimens also are discussed. Nurses play a critical role in providing patient support. Informing patients about potential EGFRI-related symptoms and dermatologic toxicities will help prepare patients for their course of treatment. In addition, nurses should provide patients with a variety of coping strategies to help manage dermatologic toxicities that will assist in enhancing patients' adherence to EGFRI treatment.
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Affiliation(s)
- Jean Boucher
- University of Massachusetts Memorial Medical Center in Worcester, USA.
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Baas JM, Krens LL, Guchelaar HJ, Ouwerkerk J, de Jong FA, Lavrijsen APM, Gelderblom H. Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review. Cancer Treat Rev 2011; 38:505-14. [PMID: 22100458 DOI: 10.1016/j.ctrv.2011.09.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Revised: 09/21/2011] [Accepted: 09/30/2011] [Indexed: 12/22/2022]
Abstract
Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient's quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity.
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Affiliation(s)
- J M Baas
- Department of Clinical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
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25
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O'Bryan KW, Ratner D. The role of targeted molecular inhibitors in the management of advanced nonmelanoma skin cancer. ACTA ACUST UNITED AC 2011; 30:57-61. [PMID: 21540021 DOI: 10.1016/j.sder.2011.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Surgical treatment remains the standard of care for nonmelanoma skin cancer and is successful for the vast majority of patients with these tumors. The treatment of patients with metastatic or unresectable nonmelanoma skin cancer, however, has until recently been based solely on traditional methods of chemotherapy and radiation. However, these methods have high rates of treatment failure, morbidity, and mortality, and alternative treatment modalities for patients with aggressive or advanced disease are needed. As in other areas of cancer therapeutics, recent research elucidating the molecular basis of cancer development, and the subsequent arrival of targeted molecular inhibitors for cancer therapy, have been met with much excitement. In this review, we seek to illuminate recent developments and future possibilities in the use of targeted molecular inhibitors for treatment of advanced squamous cell carcinoma, basal cell carcinoma, and dermatofibrosarcoma protuberans.
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Affiliation(s)
- Kevin W O'Bryan
- Columbia University Department of Dermatology, Division of Dermatologic Surgery, New York, NY 10032, USA.
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Abstract
INTRODUCTION Currently marketed epidermal growth factor receptor inhibitors (egfris) have been associated with high rates of dermatologic toxicity. METHODS We formally reviewed the literature at medline and embase. Additional searches were conducted using Internet search engines. Studies were eligible if they were randomized controlled clinical trials of egfris, specifically cetuximab and panitumumab, in which at least one arm consisted of a non-egfri treatment and rash safety data were reported. The random effects method was used to pool differences in incident rash rates. Results are summarized as differences in incident rash (egfri therapy rate minus the non-egfri therapy rate) with corresponding 95% confidence intervals (cis) for all severity grades of rash and for grades 3 and 4 rash. RESULTS Sixteen studies met the initial inclusion criteria of randomized controlled trials comparing egfri with non-egfri therapy. Seven publications that provided information on all severity grades of rash were found to have an overall difference in incident rash rate of 0.74 (95% ci: 0.68 to 0.81; p < 0.01). Thirteen studies that reported the incidence of grades 3 and 4 rash showed an overall difference in the incident rash rate of 0.12 (95% ci: 0.09 to 0.14; p < 0.01) between egfri and non-egfri therapy. Sensitivity analyses showed that the results were generally robust, but sensitive to small samples. CONCLUSIONS Results quantify the difference in rash rates between egfri and non-egfri therapy.
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Affiliation(s)
- N Mittmann
- HOPE Research Centre, Division of Clinical Pharmacology, Sunnybrook Health Sciences Centre, Toronto, ON
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Fakih M, Vincent M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. ACTA ACUST UNITED AC 2011; 17 Suppl 1:S18-30. [PMID: 20680104 PMCID: PMC2901793 DOI: 10.3747/co.v17is1.615] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, plays an important role in the control of cell growth and differentiation. Disruption of its signaling leads to neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis. EGFR is overexpressed in a variety of solid tumors, including colorectal cancer (CRC), and its overexpression is associated with poorer prognosis. One class of agents that is currently used to target EGFR in the treatment of metastatic CRC (mCRC) is the monoclonal antibodies. While the monoclonal antibody EGFR inhibitors lack many of the severe side effects commonly observed with cytotoxic chemotherapy, they are associated with a set of unique dermatological toxicities. This paper reviews the safety profile of the anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of mCRC.
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Affiliation(s)
- M Fakih
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
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White KJ, Roydhouse JK, Scott K. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor-inhibitor treatment. Clin J Oncol Nurs 2011; 15:88-96. [PMID: 21278044 DOI: 10.1188/11.cjon.88-96] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Epidermal growth factor receptor inhibitors (EGFRIs) are an increasingly important class of anticancer agents. Cutaneous toxicities, the most common adverse effects of EGFRI therapy, require dose modification or treatment cessation when moderate or severe and may compromise treatment compliance. To date, assessment has focused on physical symptoms associated with cutaneous toxicities; however, the psychosocial impact of those effects requires greater consideration. This article reviews current knowledge of assessment of cutaneous toxicities and identifies gaps in evidence, with particular focus on the psychosocial impact of cutaneous toxicities. Promising new assessment tools and approaches including the use of electronic patient-reported outcome measures are discussed, as well as implications for research in evaluating psychosocial interventions.
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Affiliation(s)
- Kathryn J White
- Cancer Institute of New South Wales, Sydney Nursing School, University of Sydney, Australia.
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29
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Lee WJ, Chi SG, Park DJ, Kim JY, Kim HY, Lee SJ, Kim DW, Kim MK, Kim JC, Lee MW. Treatment of Cultured Sebocytes with an EGFR Inhibitor Does Not Lead to Significant Upregulation of Inflammatory Biomarkers. Ann Dermatol 2011; 23:12-8. [PMID: 21738357 DOI: 10.5021/ad.2011.23.1.12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 07/28/2010] [Accepted: 07/28/2010] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) inhibitors are being used to treat malignancies originating from epithelia. Unfortunately, blocking the EGFR pathway leads to various side effects, most frequently acneiform eruptions. OBJECTIVE To probe the mechanism underlying this side effect, we investigated the effect of EGFR inhibitors on cultured sebocytes. METHODS To examine the effects of an EGFR inhibitor (cetuximab, Erbitux® 10 ng/ml) and the effects of EGFR ligands, such as epidermal growth factor (EGF, 10 ng/ml) and transforming growth factor-α (TGF-α, 5 ng/ml), on the production of inflammatory cytokines in cultured sebocytes, we used reverse transcriptase-polymerase chain reaction, immunocytofluorescence and Western blots. Outcomes included the expression of interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α), peroxisome proliferator-activated receptor-γ (PPAR-γ) and EGFR. RESULTS There were no significant differences in the expression of IL-1, IL-6, TNF-α, PPAR-γ and EGFR between (a) groups treated with an EGFR inhibitor or an EGFR ligand and (b) the control group, except for a significant increase in the expression of IL-1 in the EGF-treated group. CONCLUSION EGFR inhibitors and EGFR ligands do not provoke the expression of inflammatory biomarkers in cultured sebocytes. The role of the sebaceous glands in EGFR inhibitor-induced acneiform eruption should be investigated more thoroughly.
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Affiliation(s)
- Weon Ju Lee
- Department of Dermatology, Kyungpook National University School of Medicine, Daegu, Korea
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Wong SF, Lindgren A, Mummaneni M, Byun T, Vasko C, Arenos R, Alexson E, Osann K. A prospective crossover pilot study to evaluate the use of a topical wound gel in patients with cutaneous toxicity caused by epidermal growth factor receptor inhibitors. ACTA ACUST UNITED AC 2010; 8:202-8. [PMID: 21086877 DOI: 10.1016/j.suponc.2010.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
One of the dose-limiting toxicities of epidermal growth factor receptor inhibitors (EGFRIs) is a papulopustular rash that is often pruritic and painful. Secondary skin infection can occur from scratching to relieve the pruritus. Studies suggest that this rash might be a surrogate marker for efficacy; therefore, effective rash management is needed to allow patients to use EGFRIs without unnecessary dose modifications. In this single-center, prospective, crossover study, we evaluated the use of a topical gel (Regenecare Wound Gel) for relieving the pruritus and pain of EGFRI-induced rash among oncology patients. The secondary end points were patient satisfaction, adverse effects, and EGFRI dose modifications. At the occurrence of grade 2 skin rash, patients started applying the study gel to the right side of their face; after 1 week, they began applying it to both sides of their face for up to an additional 5 weeks. Each week, providers performed a facial evaluation and patients rated their symptoms and satisfaction on questionnaires. Of the 20 patients enrolled, 13 were evaluable. Reduction in itch at the end of week 1 was greater on the right (treated) side in 69% of patients greater on the left (untreated) side in 8%, and the same in 23% (P = 0.01). The pattern was similar for pain, but the differences were not significant. On average, patients rated the gel as being moderately to extremely effective for alleviating symptoms, improving rash appearance, and promoting healing and found it easy to apply. No adverse effects were documented. Four patients (31%) required EGFRI dose modifications because of rash. Taken together, these findings suggest that the topical wound gel is effective in relieving rash-associated itching in patients receiving EGFRIs and is associated with high patient satisfaction.
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Affiliation(s)
- Siu-Fun Wong
- Loma Linda University, School of Pharmacy, Loma Linda, California 92350, USA.
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31
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Expert Consensus on the Management of Erlotinib‐Associated Cutaneous Toxicity in the U.K. Oncologist 2009; 14:840-7. [DOI: 10.1634/theoncologist.2009-0055] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Abstract
Epidermal growth factor has an important role in the regulation of proliferation and differentiation in epidermal keratinocytes, as well as in the survival, angiogenesis and metastasis of cancer cells. Cetuximab is a chimeric monoclonal antibody selective for the epidermal growth factor receptor that induces a broad range of cellular responses that enhance tumor sensitivity to radiotherapy and chemotherapeutic agents. However, it can cause adverse events in the patient including acneiform eruption, asthenia, abdominal pain and nausea/vomiting. We report a case of severe acneiform eruption induced by cetuximab in a 56-year-old man with colorectal cancer and liver metastases.
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Affiliation(s)
- Jung Eun Lee
- Yonsei Star Skin & Laser Clinic, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Ju Lee
- Yonsei Star Skin & Laser Clinic, Yonsei University College of Medicine, Seoul, Korea
| | - Hee Jung Lee
- Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea
| | - Ju Hee Lee
- Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang Hoon Lee
- Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea
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Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: An update. J Am Acad Dermatol 2008; 58:545-70. [PMID: 18342708 DOI: 10.1016/j.jaad.2008.01.001] [Citation(s) in RCA: 140] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2007] [Revised: 01/07/2008] [Accepted: 01/10/2008] [Indexed: 12/17/2022]
Abstract
UNLABELLED Chemotherapeutic agents give rise to numerous well described adverse effects that may affect the skin, hair, mucous membranes, or nails. The mucocutaneous effects of longstanding agents have been extensively studied and reviewed. Over the last 2 decades, a number of new molecular entities for the treatment of cancer have been approved by the United States Food and Drug Administration (FDA). This article reviews the cutaneous toxicity patterns of these agents. It also reviews one drug that has not received FDA approval but is in use outside the United States and is important dermatologically. Particular emphasis is placed on the novel signal transduction inhibitors as well as on newer literature pertaining to previously described reactions. LEARNING OBJECTIVES At the completion of this learning activity, participants should able to list the newer chemotherapeutic agents that possess significant mucocutaneous side effects and describe the range of reactions that are seen with each drug. In addition, they should be able to formulate appropriate management strategies for these reactions.
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Affiliation(s)
- Noushin Heidary
- Ronald O. Perelman Department of Dermatology, New York University, New York, USA
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35
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Bianchini D, Jayanth A, Chua YJ, Cunningham D. Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker. Clin Colorectal Cancer 2008; 7:33-43. [PMID: 18279575 DOI: 10.3816/ccc.2008.n.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The human epidermal growth factor receptor (HER1/EGFR/ErbB1) signaling is aberrant and overexpressed in many solid malignancies making it an appealing target for biologic agents. Among the classes of drugs targeting EGFR are monoclonal antibodies and EGFR tyrosine kinase inhibitors, which have been shown effective and generally well tolerated in different clinical settings. The majority of patients treated with EGFR inhibitors (EGFRIs) develop specific dose-dependent skin toxicity. This side effect may lead to physical and psychosocial discomfort which can result in dose reduction or treatment interruption. The relationship between rash and clinical outcome has stimulated interest in this particular toxicity as a possible surrogate marker of efficacy in patients treated with targeted agents against EGFR. This review aims to summarize and update the current knowledge of the clinical presentation, predictive and prognostic value, and the management of EGFRI-related skin toxicity.
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Affiliation(s)
- Diletta Bianchini
- Department of Medicine, Royal Marsden Hospital, Down's Road, Sutton, Surrey, SM2 5PT UK
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36
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Doebelin B, Ly A, Allombert C, Faure M, Claudy A. Effets secondaires dermatologiques des inhibiteurs de l’EGFR. Presse Med 2008; 37:485-9. [PMID: 17601698 DOI: 10.1016/j.lpm.2007.05.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2006] [Revised: 04/27/2007] [Accepted: 05/23/2007] [Indexed: 11/23/2022] Open
Abstract
Epidermal growth cell receptors (EGFR) play a key role in tumor proliferation. Their inhibitors (anti-EGFR) are promising treatments for various types of cancers. Papulopustular follicular eruptions are the most frequent dermatological side effect and occur in 45 to 85% of patients receiving this treatment. Paronychias appear after several weeks of treatment. They are painful and impair hand and foot function. A positive correlation seems to exist between the intensity of the papulo-follicular eruption, tumor regression and survival.
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37
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Hammond-Thelin LA. Cutaneous reactions related to systemic immunomodulators and targeted therapeutics. Dermatol Clin 2008; 26:121-59, ix. [PMID: 18023775 DOI: 10.1016/j.det.2007.08.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The arrival of targeted therapeutics into the oncology clinic, while enthusiastically anticipated, introduced the oncologist to dermatologic events that can pose challenging management issues. The dermatologic effects of these targeted agents appear to be more frequent than those with cytotoxic therapy and are not uniform; that is, different agents have distinct dermatologic toxicities. Interestingly, dermatologic toxicity may correlate with antitumor activity with some of these targeted agents. The correlation of rash with response and survival in particular mandates the development of effective and appropriate management strategies. The nature and challenges of the dermatologic events observed to date with epidermal growth factor receptor inhibitors, multikinase inhibitors, proteosome inhibitors, BCR-ABL tyrosine kinase inhibitors, and immunomodulatory drugs will be addressed in this review.
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38
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Deslandres M, Sibaud V, Chevreau C, Delord J. Effets secondaires cutanés des nouvelles molécules anticancéreuses : focus sur les molécules ciblant les récepteurs tyrosine kinase et le récepteur à l’EGF. Ann Dermatol Venereol 2008; Spec No 1:16-24. [DOI: 10.1016/s0151-9638(08)70093-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Boone SL, Rademaker A, Liu D, Pfeiffer C, Mauro DJ, Lacouture ME. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 2007; 72:152-9. [PMID: 18160805 DOI: 10.1159/000112795] [Citation(s) in RCA: 134] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2007] [Accepted: 06/28/2007] [Indexed: 01/14/2023]
Abstract
Biologic agents targeting the epidermal growth factor receptor (EGFR) have emerged as a robust treatment option for various solid tumors. Despite lower systemic side effects than conventional chemotherapy, the majority of patients treated with these agents experience cutaneous toxicities, including papulopustular rashes, hair and nail changes, xerosis and pruritus, which have a significant impact on health and quality of life. Currently no consensus or management guidelines exist for these untoward events. Therefore, a retrospective survey was carried out across 110 oncology practioners in the US that were administering EGFR inhibitors. Providers were queried on the impact and management of these untoward events in their practices. Responses suggest that combination therapies (topical and oral) were more effective than either therapy alone, and also lead to a more rapid resolution of the papulopustular rash. Providers also reported that patients frequently complained of physical symptoms associated with the rash (itching and pain), and that they had a positive perception when being treated for their cutaneous side effects. The survey results support that attentive cutaneous care is important in patients treated with EGFR inhibitors, and that proactive/combined interventions may enhance quality of life and optimize consistent drug administration.
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Affiliation(s)
- Susan L Boone
- Department of Dermatology, SERIES Clinic, Northwestern University's Feinberg School of Medicine, Chicago, Ill. 60611, USA
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40
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Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 2007; 12:610-21. [PMID: 17522250 DOI: 10.1634/theoncologist.12-5-610] [Citation(s) in RCA: 248] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Epidermal growth factor receptor inhibitors (EGFRIs) have demonstrated improved overall survival in patients with non-small cell lung cancer, pancreatic cancer, and colorectal cancer; however, their use is associated with dermatologic reactions of varying severity. The similar spectrum of events observed with monoclonal antibodies and tyrosine kinase inhibitors suggests such toxicities are a class effect. While such reactions do not necessarily require any alteration in EGFRI treatment, being best addressed through symptomatic treatment, there is limited evidence on which to base such therapies. In October 2006, at an international and interdisciplinary EGFRI dermatologic toxicity forum, the underlying mechanisms of these toxicities were discussed and commonly used therapeutic interventions were evaluated. Our aim was to reach a current consensus on management strategies. A three-tiered, EGFRI-focused toxicity grading system is suggested for the purposes of therapeutic decision making, and as a framework on which to build a stepwise approach to intervention. This approach to successful management is specifically tailored to accurately categorize dermatologic toxicity associated with EGFRIs, and can be easily applied by all health care professionals. The goal is to maximize quality of life in patients who are being treated with these agents--many of whom will be on these drugs for several months or even years.
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Affiliation(s)
- Thomas J Lynch
- Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
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41
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Erupción acneiforme aguda secundaria a cetuximab con buena respuesta a metronidazol. ACTAS DERMO-SIFILIOGRAFICAS 2007. [DOI: 10.1016/s0001-7310(07)70155-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Sarkaria JN, Schwingler P, Schild SE, Grogan PT, Mladek AC, Mandrekar SJ, Tan AD, Kobayashi T, Marks RS, Kita H, Miller RC, Limper AH, Leof EB. Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer. J Thorac Oncol 2007; 2:751-7. [PMID: 17762343 DOI: 10.1097/jto.0b013e3180cc2587] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE The safety and tolerability of sirolimus combined with thoracic radiation and cisplatin was evaluated in patients with lung cancer. In parallel, the effects of sirolimus were studied in a murine model of radiation pneumonitis. MATERIALS AND METHODS The phase I trial evaluated standard three-dimensional conformal thoracic radiation therapy (60 Gy) and weekly cisplatin (25 mg/m2 i.v.) in combination with escalating doses of oral sirolimus. Sirolimus drug levels and inhibition of mTOR signaling to ribosomal S6 protein were assessed in blood. The effects of sirolimus administered during and after whole thoracic radiation of C57BL6/J mice were evaluated by monitoring mouse breathing rates and survival. RESULTS Seven patients with stage III lung cancer were accrued to the clinical study. None of the four patients treated with 2 mg/day sirolimus developed dose-limiting toxicities. Three patients were treated with 5 mg/day sirolimus, and one patient at this dose level had dose-limiting toxicity of grade 3 dysphagia. However, the maximally tolerated dose of sirolimus in this regimen was not defined because the study was terminated prematurely because of loss of funding. In the mouse experiments, concomitant sirolimus treatment was not associated with an increase in radiation-associated morbidity or mortality. CONCLUSIONS Combination therapy with sirolimus, radiation, and cisplatin was well tolerated in patients.
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Affiliation(s)
- Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
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43
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Gencoglan G, Ceylan C. Two cases of acneiform eruption induced by inhibitor of epidermal growth factor receptor. Skin Pharmacol Physiol 2007; 20:260-2. [PMID: 17641540 DOI: 10.1159/000106075] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2007] [Accepted: 05/10/2007] [Indexed: 11/19/2022]
Abstract
BACKGROUND Cetuximab is a member of a new family of antineoplastic agents that inhibit the epidermal growth factor receptor (EGF-R), and which are increasingly being used in the treatment of solid tumors. METHODS We have observed new secondary side effects. We present here 2 patients with acneiform eruption secondary to the administration of cetuximab (IMC-C225, Erbitux). The diagnoses of these patients were adenocarcinoma. RESULTS Histologically, a superficial purulent folliculitis and disordered differentiation with focal parakeratosis were observed. The follicular eruption responded favorably to treatment with 5% benzoyl peroxide and 4% erythromycin gel. These lesions healed within a few days after treatment. CONCLUSION The cutaneous adverse effects of cetuximab are similar to other EGF-R-targeted agents and result from direct interference with the functions of EGF-R signaling in the skin.
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Affiliation(s)
- G Gencoglan
- Department of Dermatology, Medical Faculty of Afyon Kocatepe University, Afyon, Turkey.
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44
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Jiménez-Puya R, Gómez-García F, Rodríguez-Bujaldón A, Moreno-Giménez J. Acute Acneiform Eruption Secondary to Cetuximab With Good Response to Metronidazole. ACTAS DERMO-SIFILIOGRAFICAS 2007. [DOI: 10.1016/s1578-2190(07)70535-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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45
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Guillot B, Bessis D. Aspects cliniques et prise en charge des effets secondaires cutanés des inhibiteurs du récepteur à l’EGF. Ann Dermatol Venereol 2006; 133:1017-20. [PMID: 17185940 DOI: 10.1016/s0151-9638(06)71093-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- B Guillot
- CHU de Montpellier, Service de Dermatologie, Hôpital Saint Eloi, 80, avenue A. Fliche, 34295 Montpellier Cedex 5.
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Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol 2006; 56:317-26. [PMID: 17141360 DOI: 10.1016/j.jaad.2006.09.005] [Citation(s) in RCA: 129] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2006] [Revised: 09/05/2006] [Accepted: 09/06/2006] [Indexed: 10/23/2022]
Abstract
The growing investigation and use of epidermal growth factor receptor (EGFR) inhibitors in anticancer therapy has been motivated by their specificity for EGFR, which improves their ability to target cancer cells and enhances their safety profile compared with many other conventional chemotherapeutic agents. However, their growing use has been accompanied by an increasing incidence of cutaneous toxicities, which can cause serious discomfort and be disabling. This review illustrates the common cutaneous side effects seen in patients receiving EGFR inhibitors and discusses various options for management. With effective management of these side effects, dermatologists can play an integral role in facilitating compliance with anti-EGFR therapy and aid with effective oncologic management.
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Affiliation(s)
- Jenny C Hu
- David Geffen School of Medicine at University of California, Los Angeles 90095, USA
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Abstract
The increased target specificity of epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is associated with the reduction or abolition of nonspecific and haematopoietic side effects. However, coincident inhibition of receptor activity in tissues that depend on EGFR signalling for normal function has undesirable consequences. Because of the key role of EGFR signalling in skin, dermatological toxicities have frequently been described with EGFRIs. The resultant significant physical and psycho-social discomfort might lead to interruption or dose modification of anticancer agents. There is an urgent need for an improved understanding of these toxicities to develop adequate staging systems and mechanistically driven therapies, and to ensure quality of life and consistent antineoplastic therapy.
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Affiliation(s)
- Mario E Lacouture
- SERIES Clinic and Cancer Skin Care Program, Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 North Saint Clair Suite 1600, Chicago, Illinois 60611, USA.
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Tscharner GG, Bühler S, Borner M, Hunziker T. Grover’s Disease Induced by Cetuximab. Dermatology 2006; 213:37-9. [PMID: 16778425 DOI: 10.1159/000092836] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2005] [Accepted: 01/20/2006] [Indexed: 11/19/2022] Open
Abstract
A 71-year-old man exhibited an acute acneiform rash affecting the face and the upper trunk about 2 weeks after starting cetuximab, an epidermal growth factor (EGF) receptor antagonist treatment for metastatic colon cancer. The skin eruption faded after stopping cetuximab and applying topical corticosteroids. The reexposure to cetuximab 3 weeks later provoked a more extended relapse of the skin rash, which then clinically and histologically corresponded to transient acantholytic dermatosis . While the acneiform cutaneous side effects of the EGF receptor antagonists are interpreted as a result of the direct interference with pilosebaceous follicle homeostasis, in this case an acrosyringium-related pathogenesis might be postulated. Applying topical corticosteroids and emollients, the cetuximab therapy could be pursued.
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Affiliation(s)
- G G Tscharner
- Department of Dermatology, University of Berne, Berne, Switzerland
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Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2006. [DOI: 10.1002/pds.1178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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