Previous studies have indicated that targeted cancer therapies have fewer oral complications and milder side effects than conventional cancer chemotherapy.
But a literature review in Oral Oncology found that most studies involving targeted cancer therapies do not focus enough on the potential oral complications of these agents, especially when they are combined with other cancer therapies (June 2011, Vol. 47:6, pp. 441-448).
Conventional chemotherapy carries a heavy toxicity burden and often produces adverse oral side effects, including mucositis, hyposalivation/xerostomia, dysphagia, pharyngitis, infection, and taste alteration, according to Amber Watters, DDS, a clinical instructor in oral and maxillofacial pathology at the New York University College of Dentistry, and colleagues from University of Illinois and Northwestern University.
Newer cancer treatments are being developed that focus on targeting tumors and controlling malignancies while minimizing toxic effects on normal tissue. Molecularly targeted cancer therapies block the growth and survival of cancer cells by interfering with specific molecules and pathways involved in carcinogenesis.
Today, targeted cancer therapies such as epidermal growth factor receptor inhibitors (EGFRI) are being used to treat solid tumors in the lung, breast, kidney, colon and rectum, and head and neck. EGFRI therapy is also used to treat epithelial cancers, including breast, colorectal, oropharyngeal, and non-small cell lung cancers and renal cell carcinoma.
Other targeted cancer treatments include vascular endothelial growth factor, monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), and multikinase inhibitors. Common targeted therapies used in clinical practice or under investigation include cetuximab, panitumumab, erlotinib, sorafenib, sunitinib malate, imatinib mesylate, bevacizumab, trastuzumab, lapatinib, and mammalian target of rapamycin (mTOR).
Testing the theory
Published studies investigating the safety of these agents have indicated that patients experience fewer oral complications with them than with conventional chemotherapies. But most of these reports focused on acute complications and offer limited information on chronic complications and survivorship issues, according to Dr. Watters.
— Amber Watters, DDS, and colleagues
To illustrate the nature, variety, and frequency of oral complications associated with targeted cancer therapies, she and her colleagues conducted a literature review on Medline/Ovid. A total of 143 studies met their inclusion criteria. Relevant articles included phase I, II, and III studies and case reports that recorded oral complications.
They found that there is little published data on the side effects of targeted therapies, and that the majority of studies in their review did not specifically address oral toxicities or include an oral clinical exam. This could lead to underreported and underinvestigated oral toxicities, the study authors noted.
"We are not aware of any reviews to date that include comprehensive data on the oral cavity side effects of targeted therapy," they wrote. "Through our review of the current literatures, it is apparent that the data collected on oral cavity side effects of targeted therapy is limited in quality and quantity."
For example, cetuximab is a recombinant human/murine mAbs directed toward EGFR and is commonly used to treat head and neck squamous cell carcinoma and colorectal cancer. Oral toxicities reported in the literature include mucositis, xerostomia, dysphagia, and pharyngitis.
"Cetuximab-associated mucositis appears to present with a general erythema and sensitivity that may be less ulcerative of nonkeratinized mucosa than that typically seen with cytotoxic chemotherapy and radiation therapy," the authors wrote.
However, a meta-analysis reported that cetuximab plus radiotherapy (RT) has a higher prevalence of mucositis compared with RT with cytotoxic therapy or RT alone (Cancer, March 15, 2009, Vol. 115:6, pp. 1286-1299).
In general, however, "the majority of the phase I-III studies do not mention oral adverse events associated with cetuximab, which may be due to underreporting or to less severe or frequent adverse events compared to other EGFR tyrosine or multikinase inhibitors," the authors of the current study wrote.
Multiple complications
Some of the other targeted therapy agents were found to prompt a number of oral complications, according to the study authors. For example:
A large, randomized, placebo-controlled phase III trial of patients treated with the mTOR everolimus for relapsed renal cell carcinoma after treatment with vascular endothelial growth factor (VEGF) targeted therapy found that stomatitis was reported in 40% of all patients, with 3% experiencing grade 3 reactions (Lancet, August 9, 2008, Vol. 372:9637, pp. 449-456).
A phase I trial of the mTOR ridaforolimus reported mouth sores -- including mouth pain, mucosal inflammation, and stomatitis -- in 78% of patients (Journal of Clinical Oncology, January 20, 2008, Vol. 26:3, pp. 361-367).
Other studies have found that sorafenib tosylate -- a small molecule multikinase inhibitor being investigated for treating thyroid carcinoma; breast, lung, and head and neck cancers; and melanoma -- has number of oral side effects, including voice changes/hoarse voice, taste alterations, mucositis/stomatitis, tongue pain, throat pain, and tooth pain, and one study reported mild gum bleeding (Journal of Clinical Oncology, June 1, 2007, Vol. 25:16, pp. 2191-2197; April 1, 2009, Vol. 27:10, pp. 1675-1684).
Bevacizumab is an anti-VEGF immunoglobulin G (IgG) mAbs that inhibits angiogenesis. Adverse effects are hematological toxicities, neutropenia, and hemorrhage, with hypertension being most frequently reported. Wound-healing complications are possible due to bevacizumab's antiangiogenic properties and may have a possible effect on the jaw when healing after dental surgery (Journal of Clinical Oncology, August 20, 2008, Vol. 26:24, pp. 4037-4038). Coadministration with IV bisphosphonates has been identified as a possible contributor to development of bisphosphonate-related osteonecrosis of the jaw (Oncology, March 2009, Vol. 76:3, pp. 209-211).
"The difficulty with determining the prevalence of oral side effects from drug safety studies lies in the limited studies and potential unreported or uninvestigated symptoms," the study authors wrote. "Many phase I-III studies limit oral symptom investigation to ‘mucositis/stomatitis,' which does not include other potential oral complications such as xerostomia, dysgeusia, odynophagia, and pharyngitis."
Although oral mucosal manifestations that limit therapy have not been associated with use of targeted therapies alone, mucosal damage may impact quality of life and oral intake, and may be painful, particularly when multimodality therapy is used, they added.
"It is important to categorize the entire spectrum of drug-related toxicities, including oropharyngeal toxicities, in order to convey an accurate message to patients regarding the nature of their treatment, and to develop adjunctive therapy to prevent or minimize these toxicities," the researchers concluded.
