Review: side effects of approved molecular targeted therapies in solid cancers.

Major advances have been achieved in the field of biologically based therapies for cancer in the last few years, and some of the recently approved molecular-targeted therapies are now being used in daily clinical practice. These molecular targets are also expressed in normal cells, which explains the different grades of toxicity, resulting from the disruption of normal cellular function. In general, targeted molecular therapies have good toxicity profiles, but some patients are exquisitely sensitive to these drugs and can develop particular and severe toxicities. In this article, we review the toxicity and safety of various small molecules and monoclonal antibodies used in solid tumors, with discussion of the pathophysiology, correlation with response, and strategies for prevention and management.

[1]  E. Raymond,et al.  Tyrosine kinase inhibition and grey hair , 2003, The Lancet.

[2]  N. Magné,et al.  Pharmacological background of EGFR targeting. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  M. Heinrich,et al.  SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. , 2003, Blood.

[4]  M. Blute Sunitinib in patients with metastatic renal cell carcinoma , 2006 .

[5]  C. Sawyers,et al.  Targeted cancer therapy , 2004, Nature.

[6]  T. Mehlman,et al.  Structural evidence that endothelial cell growth factor I is the precursor of both endothelial cell growth factor a and acidic fibroblast growth factor ( protein sequence / mass spectrometry / heparin ) , 2022 .

[7]  L. Crinò,et al.  Efficacy and tolerability of gefitinib in pretreated elderly patients with advanced non-small-cell lung cancer (NSCLC) , 2004, British Journal of Cancer.

[8]  Y. Izumi,et al.  Phase II trial of gemcitabine and docetaxel in patients with completely resected stage IIA–IIIA non-small-cell lung cancer , 2007, Cancer Chemotherapy and Pharmacology.

[9]  Sang-We Kim,et al.  Cutaneous side effects in non-small cell lung cancer patients treated with Iressa (ZD1839), an inhibitor of epidermal growth factor. , 2003, Acta dermato-venereologica.

[10]  Carmen Birchmeier,et al.  Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Alexandrescu,et al.  Effect of treatment with a colloidal oatmeal lotion on the acneform eruption induced by epidermal growth factor receptor and multiple tyrosine‐kinase inhibitors , 2006, Clinical and experimental dermatology.

[12]  A. Harris,et al.  Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Carmen Birchmeier,et al.  ErbB2 pathways in heart and neural diseases. , 2003, Trends in cardiovascular medicine.

[14]  D. Opel,et al.  Neuregulins Promote Survival and Growth of Cardiac Myocytes , 1998, The Journal of Biological Chemistry.

[15]  F. Kabbinavar,et al.  Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  David Cameron,et al.  2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial , 2007, The Lancet.

[17]  L. Presta,et al.  Humanization of an anti-p185HER2 antibody for human cancer therapy. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[18]  G. Peters,et al.  Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  P. Russo Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma , 2006 .

[20]  M. Dewhirst,et al.  SU5416 Delays Wound Healing Through Inhibition of TGF-β Activation , 2002 .

[21]  B. Vincenzi,et al.  Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial , 2006, British Journal of Cancer.

[22]  K. Herrup,et al.  Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. , 1995, Science.

[23]  K. Gelmon,et al.  A multi-centre phase II trial of pegylated liposomal doxorubicin and trastuzumab in HER-2 over-expressing metastatic breast cancer (MBC) , 2004 .

[24]  K. Flaherty,et al.  Mechanisms of hypertension associated with BAY 43-9006. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  U. Rodeck,et al.  The EGF receptor - an essential regulator of multiple epidermal functions. , 2000, European journal of dermatology : EJD.

[26]  Z. Hua Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer , 2006 .

[27]  N. Spector,et al.  Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells , 2005, Oncogene.

[28]  U. Rodeck,et al.  Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage. , 2003, Cancer research.

[29]  D. Sane,et al.  Angiogenic growth factors and hypertension , 2004, Angiogenesis.

[30]  G. Pond,et al.  Pegylated liposomal doxorubicin and trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trial. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  A. Oza,et al.  Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[32]  C. Ozcan,et al.  Reversible posterior leukoencephalopathy syndrome and bevacizumab. , 2006, The New England journal of medicine.

[33]  David A. Smith,et al.  Clinical activity of GW572016 in EGF10003 in patients with solid tumors. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  Prakash Chinnaiyan,et al.  Dual-Agent Molecular Targeting of the Epidermal Growth Factor Receptor (EGFR) , 2004, Cancer Research.

[35]  V. Valero,et al.  Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  E. Raymond,et al.  Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  M. Dewhirst,et al.  SU5416 delays wound healing through inhibition of TGF-beta 1 activation. , 2002, Cancer biology & therapy.

[38]  M. Berger,et al.  Results of an analysis of cardiac function in 2,812 patients treated with lapatinib. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  H. Struijker‐Boudier,et al.  The Microcirculation and Hypertension , 1992 .

[40]  A. Friedl,et al.  Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. , 1991, Circulation.

[41]  Kenneth J. Hillan,et al.  Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene , 1996, Nature.

[42]  R. Figlin,et al.  Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  J. Hainsworth,et al.  A phase I study of the dual kinase inhibitor GW572016 in combination with paclitaxel (EGF10009). , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  Tim Eisen,et al.  Kinase Inhibition with BAY 43–9006 in Renal Cell Carcinoma , 2004, Clinical Cancer Research.

[45]  J. Watson,et al.  Cloning and Biological Activity of Epigen, a Novel Member of the Epidermal Growth Factor Superfamily* , 2001, The Journal of Biological Chemistry.

[46]  A. El-Khoueiry,et al.  Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  H. S. Struijker Boudier,et al.  The microcirculation and hypertension. , 1992, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[48]  A. Halpern,et al.  Cutaneous side‐effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225 , 2001, The British journal of dermatology.

[49]  G. Lip,et al.  The hypercoagulable state of malignancy: pathogenesis and current debate. , 2002, Neoplasia.

[50]  R. Perez-soler Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? , 2003, Oncology.

[51]  M. Berger,et al.  Lapatinib plus capecitabine for HER2-positive advanced breast cancer. , 2006, The New England journal of medicine.

[52]  Hong Ma,et al.  Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways , 2002, Oncogene.

[53]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[54]  C. Hudis,et al.  Cardiac dysfunction in the trastuzumab clinical trials experience. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  D. Gossard,et al.  Subungueal-Splinter Hemorrhage an Early Sign of Thromboangitis Obliterans , 1981, Angiology.

[56]  H. Burris,et al.  Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. , 2004, The oncologist.

[57]  Susumu Minamisawa,et al.  ErbB2 is essential in the prevention of dilated cardiomyopathy , 2002, Nature Medicine.

[58]  G. Giaccone,et al.  Follicular and epidermal alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor , 2002, The British journal of dermatology.

[59]  Robert Gray,et al.  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. , 2006, The New England journal of medicine.

[60]  D. Goeddel,et al.  Vascular endothelial growth factor is a secreted angiogenic mitogen. , 1989, Science.

[61]  E. Van Cutsem,et al.  Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[62]  G. Inglessis,et al.  Clinical, histochemical, and ultrastructural correlation in septal endomyocardial biopsies from chronic chagasic patients: detection of early myocardial damage. , 1987, American heart journal.

[63]  J. Folkman,et al.  Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. , 1984, Science.

[64]  Brian H Annex,et al.  The VIVA Trial Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis , 2003 .

[65]  K. Shen,et al.  Adjuvant Docetaxel or Vinorelbine with or without Trastuzumab for Breast Cancer , 2008 .

[66]  M. Kris,et al.  ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[67]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[68]  R. Playford,et al.  Growth factors and trefoil peptides in gastrointestinal health and disease. , 2004, Current opinion in pharmacology.

[69]  O. Frazier,et al.  Left ventricular unloading alters receptor tyrosine kinase expression in the failing human heart. , 2002, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[70]  R. Tsien,et al.  Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor , 1987, Nature.

[71]  E K Rowinsky,et al.  Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  L R Caplan,et al.  A reversible posterior leukoencephalopathy syndrome. , 1996, The New England journal of medicine.

[73]  L. Saltz,et al.  Irinotecan plus fluorouracil/leucovorin for metastatic colorectal cancer: a new survival standard. , 2001, The oncologist.

[74]  B. Wörmann,et al.  Trastuzumab and breast cancer. , 2001, The New England journal of medicine.

[75]  D. Stupack,et al.  Role of Raf in Vascular Protection from Distinct Apoptotic Stimuli , 2003, Science.

[76]  Y. Tabata,et al.  Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis. , 2005, Gastroenterology.

[77]  Kunio Matsumoto,et al.  Angiogenesis inhibitors: from laboratory to clinical application. , 2005, Biochemical and biophysical research communications.

[78]  H. Granger,et al.  VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. , 1998, American journal of physiology. Heart and circulatory physiology.

[79]  P. Novotny,et al.  Does tetracycline prevent/palliate epidermal growth factor receptor (EGFR) inhibitor-induced rash? A phase III trial from the North Central Cancer Treatment Group (N03CB) , 2007 .

[80]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity , 1975, Nature.

[81]  Stephen W Dusza,et al.  Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. , 2006, Journal of the American Academy of Dermatology.

[82]  J. Desai,et al.  Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors , 2006, Annals of Internal Medicine.

[83]  J. López-Picazo,et al.  Acneiform lesions secondary to ZD1839, an inhibitor of the epidermal growth factor receptor , 2004, Clinical and experimental dermatology.

[84]  R. Figlin,et al.  Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. , 2004, International journal of radiation oncology, biology, physics.

[85]  Alain Spatz,et al.  Cutaneous side-effects of kinase inhibitors and blocking antibodies. , 2005, The Lancet. Oncology.

[86]  Motonori Yamaguchi,et al.  Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition. , 2003, Anticancer research.

[87]  P. Goss,et al.  Lapatinib: current status and future directions in breast cancer. , 2006, The oncologist.

[88]  L. Norton,et al.  Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[89]  H. Granger,et al.  VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. , 1998, American Journal of Physiology.

[90]  Xin Huang,et al.  Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial , 2006, The Lancet.

[91]  H. Abalı,et al.  Bevacizumab, bleeding, thrombosis, and warfarin. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[92]  A. Takaoka,et al.  Comparing antibody and small-molecule therapies for cancer , 2006, Nature Reviews Cancer.

[93]  H. Dvorak,et al.  Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. , 1983, Science.

[94]  M. Ebina,et al.  Severe acute interstitial pneumonia and gefitinib , 2003, The Lancet.

[95]  A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer , 2005, British Journal of Cancer.

[96]  J. Rigas,et al.  Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[97]  M. Ychou,et al.  Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours , 2004, The British journal of dermatology.

[98]  M. Lacouture Mechanisms of cutaneous toxicities to EGFR inhibitors , 2006, Nature Reviews Cancer.

[99]  Edward S. Kim,et al.  Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. , 2007, The oncologist.

[100]  D. Stern,et al.  Specificity within the EGF family/ErbB receptor family signaling network , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[101]  Roy S Herbst,et al.  Monoclonal antibodies to target epidermal growth factor receptor–positive tumors , 2002, Cancer.

[102]  B. Gilchrest,et al.  SCF/c‐kit signaling is required for cyclic regeneration of the hair pigmentation unit , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[103]  C. Agustí,et al.  Epidermal growth factor system regulates mucin production in airways. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[104]  M. Hidalgo,et al.  Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[105]  Greg Yothers,et al.  Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. , 2005, The New England journal of medicine.

[106]  A. Kimyai-Asadi,et al.  Follicular toxic effects of chimeric anti-epidermal growth factor receptor antibody cetuximab used to treat human solid tumors. , 2002, Archives of dermatology.

[107]  G. Hughes,et al.  Prevalence and clinical significance of subungual splinter haemorrhages in patients with the antiphospholipid syndrome. , 1995, Clinical and experimental rheumatology.

[108]  R. Herbst,et al.  Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.