Cesar A. Migliorati

Updated clinical practice guidelines for the prevention and treatment of mucositis

Considerable progress in research and clinical application has been made since the original guidelines for managing mucositis in cancer patients were published in 2004, and the first active drug for the prevention and treatment of this condition has been approved by the United States Food and Drug Administration and other regulatory agencies in Europe and Australia. These changes necessitate an updated review of the literature and guidelines. Panel members reviewed the biomedical literature on mucositis published in English between January 2002 and May 2005 and reached a consensus based on the criteria of the American Society of Clinical Oncology. Changes in the guidelines included recommendations for the use of palifermin for oral mucositis associated with stem cell transplantation, amifostine for radiation proctitis, and cryotherapy for mucositis associated with high‐dose melphalan. Recommendations against specific practices were introduced: Systemic glutamine was not recommended for the prevention of gastrointestinal mucositis, and sucralfate and antimicrobial lozenges were not recommended for radiation‐induced oral mucositis. Furthermore, new guidelines suggested that granulocyte–macrophage‐colony stimulating factor mouthwashes not be used for oral mucositis prevention in the transplantation population. Advances in mucositis treatment and research have been complemented by an increased rate of publication on mucosal injury in cancer. However, additional and sustained efforts will be required to gain a fuller understanding of the pathobiology, impact on overall patient status, optimal therapeutic strategies, and improved educational programs for health professionals, patients, and caregivers. These efforts are likely to have significant clinical and economic impact on the treatment of cancer patients. Cancer 2007;109:820–31.

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy

Mucositis is a highly significant, and sometimes dose‐limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis.

Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment

We present current knowledge of bisphosphonate-associated osteonecrosis, a new oral complication in oncology. It was first described in 2003, and hundreds of cases have been reported worldwide. The disorder affects patients with cancer on bisphosphonate treatment for multiple myeloma or bone metastasis from breast, prostate, or lung cancer. Bisphosphonate-associated osteonecrosis is characterised by the unexpected appearance of necrotic bone in the oral cavity. Osteonecrosis can develop spontaneously or after an invasive surgical procedure such as dental extraction. Patients might have severe pain or be asymptomatic. Symptoms can mimic routine dental problems such as decay or periodontal disease. Intravenous use of pamidronate and zoledronic acid is associated with most cases. Other risk factors include duration of bisphosphonate treatment (ie, 36 months and longer), old age in patients with multiple myeloma, and a history of recent dental extraction. We also discuss pathobiology, clinical features, management, and future directions for the disorder.

Kaposi's sarcoma of the oral cavity: a study of 134 patients with a review of the pathogenesis, epidemiology, clinical aspects, and treatment.

Since our first description and profile of patients with Kaposis sarcoma (KS) in 1984, the relative rate of KS in patients with the acquired immunodeficiency syndrome has dropped from 34% to 20%. However, the absolute number is increasing. The pathogenesis of KS is still obscure, and its interaction with the human immunodeficiency virus infection remains unclear. Cause of death is usually opportunistic infections in both endemic and epidemic KS. The most common intraoral site is the palate, which is involved in 95% of our cases. The oral cavity may be the only or first site of KS, and therefore, becomes important in the diagnosis. More than 20% of our current patient population had the oral cavity as the initial site of manifestation. Because of functional impairment, bleeding, pain, or cosmetic reasons, treatment is frequently required. There are many modalities used, including chemotherapy, radiation, and laser resection. Radiation appears to be a most effective and practical control measure for oral KS.

Pharmacovigilance and reporting oversight in US FDA fast- track process: bisphosphonates and osteonecrosis of the jaw

More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0.1% to 1.8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed.

Oral manifestations of tumor and opportunistic infections in the acquired immunodeficiency syndrome (AIDS): Findings in 53 homosexual men with Kaposi's sarcoma

Fifty-three homosexual men with Kaposis sarcoma (KS) were studied. Twenty-seven had biopsy-proved oral KS, the palate being the most common site. Past or present infections with cytomegalovirus, hepatitis, venereal diseases, and gastrointestinal microorganisms occurred in more than 70%. Oral candidiasis was confirmed in 57%. Heavy marijuana smoking was the most common habit. Transmission of AIDS is thought to be by a viral agent. Precautions involving the use of gloves, eyeglasses, and masks, similar to those recommended for the management of patients with hepatitis B, are urged.

Toluidine blue staining in the detection of oral precancerous and malignant lesions

One hundred thirty-two consecutive patients suspected of having malignant or precancerous oral lesions were studied by comparing toluidine blue dye uptake clinically with a simultaneous biopsy. The histopathologic diagnosis confirmed 57 squamous carcinomas, 42 epithelial dysplasias, and 33 benign mucosal changes. Overall accuracy of the toluidine blue uptake was 91%. In the dysplastic and malignant lesions the false negatives were 2%, and there were 30% false positives in the benign lesions. It was concluded that toluidine blue staining is a useful adjunct to careful examination, clinical judgment, and biopsy.

Osteonecrosis of the jaw and bisphosphonates in cancer: a narrative review

Bisphosphonate-associated osteonecrosis (BON) is a complication that almost exclusively affects the jaw bones. The clinical presentation of BON often mimics that of other conditions, such as routine dental disease, osteoradionecrosis or avascular necrosis; therefore, diagnosis can be difficult. As this complication has only been recognized within the past 10 years, management strategies for patients with BON are poorly defined. Physicians must choose between continuing the bisphosphonate therapy (to reduce the risk of skeletal complications in patients with metastatic bone disease or osteoporosis) and discontinuing the drug (to possibly improve the odds for tissue healing). A conservative or aggressive management strategy must be chosen with limited evidence that the outcome of either strategy will be successful. BON is most prevalent in patients with cancer using intravenous nitrogen-containing bisphosphonates. The pathobiology of this complication is not fully understood and the diagnosis relies on the clinical manifestations of the condition. Future research should focus on the pathobiological mechanisms involved in the development of BON, which could help explain why this complication affects only a small number of those who use bisphosphonates, and also suggest strategies for prevention and management.

A systematic review of bisphosphonate osteonecrosis (BON) in cancer

PurposeThis systematic review aims to examine the prevalence of bisphosphonate osteonecrosis (BON) in the cancer population, prevention and treatment protocols, and quality of life issues.MethodsA search of MEDLINE/PubMed and EMBASE form October 2003 to December 31, 2008 was conducted with the objective of identifying publications that contained original data regarding BON.ResultsA total of 28 publications fulfilled inclusion criteria, but only 22 were used for prevalence analysis. No randomized controlled clinical trials, meta-analysis, or quality of life papers were found that contained information regarding either prevalence or treatment protocols for the management of BON. The overall weighted prevalence of BON included a sample of 39,124 patients with a mean weighted prevalence of 6.1%. The weighted prevalence was 13.3% for studies with documented follow-up with a sample size of 927 individuals. The weighted prevalence in studies with undocumented follow-up was 0.7% in a sample of 8,829 chart reviews. Epidemiological studies evaluated a total of 29,368 individual records, and the weighted BON prevalence was 1.2%.ConclusionsHigh-quality studies are needed to accurately characterize the prevalence of BON, and to determine effective treatment protocols.

The role of alternative and natural agents, cryotherapy, and/or laser for management of alimentary mucositis

Goals of workTo review the literature and update the current guidelines of alternative/natural agents, cryotherapy, and/or laser therapy in the management of alimentary mucositis (AM).Materials and methodsThe original guidelines developed by the Multinational Association for Supportive Care in Cancer (MASCC)/International Society for Oral Oncology (ISOO) mucositis study group were the basis for this study. A medical librarian conducted an initial Medline search to identify research articles published between 2002 and 2005 in English language. A search term combination that included stomatitis, mucositis, mucous membrane, neoplasm, lasers, complimentary therapies, amino acids, antioxidants, vitamins, minerals, plant extracts, and cryotherapy was conducted. This initial search identified articles with a strong scientific methodology that included both preclinical and clinical research. Using standardized scoring forms, authors reviewed and scored individual articles. A consensus result of the review was achieved in a meeting of reviewers in June of 2005.ResultsThe initial search identified a total of 167 new articles. Of these, 14 were selected and reviewed: alternative/natural therapy (one preclinical study); cryotherapy (four clinical studies); lasers (two clinical studies); and alternative/natural agents (seven clinical studies). A new guideline could be established for the use of cryotherapy in the management of AM in hematopoietic stem cell transplant (HSCT) patients receiving melphalan in the conditioning phase.ConclusionThe rapid progress in the understanding of AM created a need for new prevention and management protocols. Frequent literature review is now necessary to identify agents and protocols being developed in this important area of supportive care in cancer.