Nikhil G. Rao

Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients

PurposeThe aim of this project was to develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis (OM) in cancer patients.MethodsA systematic review of the available literature was conducted. The body of evidence for the use of each agent, in each setting, was assigned a level of evidence. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, or no guideline possible.ResultsA recommendation was developed in favor of patient-controlled analgesia with morphine in hematopoietic stem cell transplant (HSCT) patients. Suggestions were developed in favor of transdermal fentanyl in standard dose chemotherapy and HSCT patients and morphine mouth rinse and doxepin rinse in head and neck radiation therapy (H&N RT) patients. Recommendations were developed against the use of topical antimicrobial agents for the prevention of mucositis. These included recommendations against the use of iseganan for mucositis prevention in HSCT and H&N RT and against the use of antimicrobial lozenges (polymyxin–tobramycin–amphotericin B lozenges/paste and bacitracin–clotrimazole–gentamicin lozenges) for mucositis prevention in H&N RT. Recommendations were developed against the use of the mucosal coating agent sucralfate for the prevention or treatment of chemotherapy-induced or radiation-induced OM. No guidelines were possible for any other agent due to insufficient and/or conflicting evidence.ConclusionAdditional well-designed research is needed on prevention and management approaches for OM.

Radiotherapy influences local control in patients with desmoplastic melanoma

Desmoplastic melanoma may have a high risk of local recurrence after wide excision. The authors hypothesized that adjuvant radiotherapy (RT) would improve local control in patients with desmoplastic melanoma, resulting in at least a 10% absolute decrease in local recurrence rate.

Risk Factors for Percutaneous Endoscopic Gastrostomy Tube Placement During Chemoradiotherapy for Oropharyngeal Cancer

IMPORTANCE Patients with oropharyngeal squamous cell carcinoma undergoing chemoradiotherapy may require percutaneous endoscopic gastrostomy (PEG) tube placement because of dehydration or significant weight loss. OBJECTIVES To determine the need for the reactive placement of a PEG tube during chemoradiotherapy for oropharyngeal cancer and to identify patient or tumor factors associated with reactively requiring the placement of a PEG tube. DESIGN, SETTING, AND PARTICIPANTS Single-institution retrospective review of 297 patients treated with intensity-modulated radiation therapy and concurrent chemotherapy for oropharyngeal squamous cell carcinoma between May 1, 2004, and June 30, 2012, with a minimum follow-up period of 3 months. EXPOSURE Placement of a PEG tube. MAIN OUTCOMES AND MEASURES Logistic regression analysis was used to identify independent risk factors associated with symptomatic requirement for the reactive placement of a PEG tube. RESULTS In total, 128 patients did not receive a prophylactic PEG tube within 10 days of initiation of chemoradiotherapy. Fifteen of 128 patients (11.7%) required the reactive placement of a PEG tube during or within 3 months of chemoradiotherapy. The median time to PEG tube removal was 3.3 months, and 14 of 15 patients had their PEG tube removed at the last follow-up analysis. Independent risk factors for PEG tube placement included the following: accelerated irradiation fractionation (odds ratio, 4.3; 95% CI, 1.1-16.5; P = .04), a tumor T classification of 3 or higher (odds ratio, 3.5; 95% CI, 1.0-11.9; P = .04), a cumulative cisplatin dose of 200 mg/m² or higher (odds ratio, 6.7; 95% CI, 1.2-36.7; P = .03), and a body mass index (calculated as weight in kilograms divided by height in meters squared) of less than 25 (odds ratio, 5.8; 95% CI, 1.4-23.9; P = .02). CONCLUSIONS AND RELEVANCE Although the overall risk is low, a body mass index of less than 25, accelerated irradiation fractionation, a tumor T classification of 3 or higher, and a cumulative cisplatin dose of 200 mg/m² or higher are associated with symptomatic need for the reactive placement of a PEG tube in patients with oropharyngeal cancer.

The Florida Melanoma Trial I: A Prospective Multicenter Phase I/II Trial of Postoperative Hypofractionated Adjuvant Radiotherapy with Concurrent Interferon-Alfa-2b in the Treatment of Advanced Stage III Melanoma with Long-Term Toxicity Follow-Up

Radiotherapy (RT) and interferon-alfa-2b (IFN α-2b) have individually been used for adjuvant therapy stage III melanoma with high-risk pathologic features. We hypothesized that concurrent adjuvant RT and IFN α-2b may decrease the risk of regional recurrence following surgery with acceptable toxicity. A prospective multicenter phase I/II study was conducted to evaluate hypofractionated RT with concurrent IFN. Induction IFN α-2b, 20 MU/m2/d, was administered IV ×5 consecutive days every week for 4 weeks. Next, RT 30 Gy in 5 fractions was given with concurrent IFN α-2b, 10 MU/m2 SQ 3 times per week on days alternating with RT. Subsequent maintenance therapy consisted of adjuvant IFN α-2b, 10 MU/m2 SQ 3 times per week to a total of 1 year. To fully evaluate patterns of failure, long-term follow-up was conducted for up to 10 years. A total of 29 consenting patients were enrolled between August 1997 and March 2000. The maximum (worst) grade of acute nonhematologic toxicity during concurrent RT/IFN α-2b (and up to 2 weeks post RT) was grade 3 skin toxicity noted in 2 patients (9%). Late effects were limited. Probability of regional control was 78% (95% CI: 55%–90%) at 12 months. The median follow-up (range) was 80 (51–106) months among ten survivors (43%). The median overall survival was 34.5 months while the median failure-free survival was 19.9 months. Postoperative concurrent hypofractionated RT with IFN α-2b for advanced stage III melanoma appears to be associated with acceptable toxicity and may provide reasonable in-field control in patients at high risk of regional failure.

The Role of Radiation Therapy in the Management of Cutaneous Melanoma

Radiation therapy plays an integral role in the management of melanoma. Radiation therapy is infrequently needed for the treatment of the primary site, but there are occasions when it is appropriate. The role of adjuvant radiation therapy to resected nodal basins is becoming clearer from recent randomized data for patients at high risk. The role of radiotherapy combined with radiosensitizers, biologic or with hyperthermia, continues to evolve. Radiation therapy plays a vital role in the treatment of brain metastases and is useful for other systemic metastases. Emerging technology such as stereotactic radiation therapy may be useful in achieving durable palliation for selected patients.

Phase II multicenter trial of Caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer

PURPOSE We conducted a phase II multicenter study evaluating Caphosol in patients receiving head and neck radiation (H/N RT) +/- chemotherapy or biologic sensitizer. MATERIALS/METHODS The primary endpoint of the study tested the rate of functional mucositis (WHO grade > or equal to 2) with the hypothesis that <75% of patients would develop > or equal to 2 mucositis with Caphosol compared with a historical rate of >90%. New methods were applied with higher than historic rigor. 5 Institutions were included in this study: Moffitt Cancer Center (MCC), MD Anderson Cancer Center (MDACC), Duke University Cancer Center (DUCC), University of Florida (UF) and Temple University Cancer Center (TUCC). Caphosol was taken by patients at least 4 times a day and up to 10 times per day commencing with day 1 of RT and for a total duration of 8 weeks after completion of RT. Detailed questionnaires were completed weekly by patients and a unique algorithm was used to generate the WHO grade of mucositis. RESULTS 98 Patients were enrolled in the study. 59/98 (60%) patients were evaluable for the primary endpoint giving us 80% power. All evaluable patients experienced WHO grade > or equal to 2 mucositis and the trial failed to reject the null hypothesis. > or equal to 2 mucositis rates at weeks 2, 4, 6, 11 and 15 were as follows: 45%, 90%, 98%, 71%, 50%. CONCLUSION We were unable to demonstrate that Caphosol significantly reduced WHO grade 2 or higher mucositis below a 90% historic rate. We are not surprised with this finding given our rigorous methodology in grading.

Clinicopathologic Predictors of Survival in Patients with Desmoplastic Melanoma

Background and Objectives Desmoplastic melanoma is a unique subtype of melanoma which typically affects older patients who often have comorbidities that can adversely affect survival. We sought to identify melanoma-specific factors influencing survival in patients with desmoplastic melanoma. Methods Retrospective review from 1993 to 2011 identified 316 patients with primary desmoplastic melanoma. Clinicopathologic characteristics were correlated with nodal status and outcome. Results Fifty-five patients (17.4%) had nodal disease: 33 had a positive sentinel lymph node biopsy and 22 developed nodal recurrences (no sentinel lymph node biopsy or false-negative sentinel lymph node biopsy). Nodal disease occurred more often in younger patients and in cases with mixed compared with pure histology (26.7% vs. 14.6%); both of these variables significantly predicted nodal status on multivariable analysis (p<0.05). After a median follow-up of 5.3 years, recurrence developed in 87 patients (27.5%), and 111 deaths occurred. The cause of death was known in 79 cases, with 47 deaths (59.5%) being melanoma-related. On multivariable analysis, Breslow thickness, mitotic rate ≥1/mm2 and nodal status significantly predicted melanoma-specific survival (p<0.05). Conclusions Nodal status predicts melanoma-specific survival in patients with desmoplastic melanoma. However, since patients with desmoplastic melanoma represent an older population, and a considerable proportion of deaths are not melanoma-related (40.5%), comorbidities should be carefully considered in making staging and treatment decisions in this population.

Novel treatments for melanoma brain metastases.

BACKGROUND The development of brain metastases is common in patients with melanoma and is associated with a poor prognosis. Treating patients with melanoma brain metastases (MBMs) is a major therapeutic challenge. Standard approaches with conventional chemotherapy are disappointing, while surgery and radiotherapy have improved outcomes. METHODS In this article, we discuss the biology of MBMs, briefly outline current treatment approaches, and emphasize novel and emerging therapies for MBMs. RESULTS The mechanisms that underlie the metastases of melanoma to the brain are unknown; therefore, it is necessary to identify pathways to target MBMs. Most patients with MBMs have short survival times. Recent use of immune-based and targeted therapies has changed the natural history of metastatic melanoma and may be effective for the treatment of patients with MBMs. CONCLUSIONS Developing a better understanding of the factors responsible for MBMs will lead to improved management of this disease. In addition, determining the optimal treatments for MBMs and how they can be optimized or combined with other therapies, along with appropriate patient selection, are challenges for the management of this disease.

Effect of prophylactic fluconazole on oral mucositis and candidiasis during radiation therapy for head-and-neck cancer

PURPOSE Radiation therapy (RT) or chemoradiation therapy (CRT) for carcinoma of the head and neck can result in high rates of candidiasis and mucositis. Prophylactic fluconazole (FCZ) has been shown to reduce the incidence of candidiasis. We report our outcomes of patients with head-and-neck cancer undergoing CRT treated prophylactically with FCZ. METHODS AND MATERIALS An institutional review board-approved database of head-and-neck cancer patients treated with RT or CRT was reviewed to identify patients treated between 2004 and 2009 who received at least 50 Gy to approximately two-thirds of the oral cavity or oropharynx mucosa. Eligible patients were divided into 2 groups: the usual care group and the prophylaxis group. The primary endpoints were the incidence of mucositis and candidiasis. RESULTS A total of 181 patients were eligible for analysis: 72 patients in the prophylactic group and 109 patients in the usual care group. Patient characteristics and radiation dose were comparable between groups. RT alone was given in 28 patients (16%). Mucositis data were available in 161 (89%) patients. Grade 2 or higher mucositis was seen in 131 (81%) patients. Prophylactic FCZ had significantly decreased grade 2 or higher mucositis. In the usual care group and prophylaxis group patients, 83 of 93 patients (89.3%) and 48 of 68 patients (70.6%), respectively, developed grade 2 or higher mucositis (P = .003). CONCLUSIONS Prophylactic administration of FCZ twice weekly during CRT for head-and-neck cancer reduces incidence of mucositis and thrush.

Normal Tissue Complications and Protection in Head and Neck Cancer Patients

It has been long recognized that radiotherapy, surgery, and chemotherapy for head and neck (H&N) cancer cause a wide range of acute and late morbidities. These effects impact general and H&N-specific symptoms, quality of life, and critical functions. The increasing use of altered fractionation and chemoradiation has led to a substantial increase in both acute and late toxicity. Countering this is the growing use of intensity modulated radiation which has lowered dry mouth-related issues, and targeted agents which are associated with less complex/lower burden toxicity profiles. In this chapter, we discuss issues in toxicity measures and reporting methods. We also discuss the management of mucositis, swallowing disorders, and osteonecrosis.