Lactobacillus brevis CD2 lozenges reduce radiation- and chemotherapy-induced mucositis in patients with head and neck cancer: A randomized double-blind placebo-controlled study,☆☆

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Abstract

Background

Oral mucositis is a frequent and serious complication in patients receiving chemo-radiotherapy for head and neck squamous cell carcinoma. This study evaluated the effects of administering Lactobacillus brevis CD2 lozenges on the incidence and severity of mucositis and tolerance to chemo-radiotherapy.

Methods

Two hundred patients suitable for chemo-radiotherapy were enrolled in a randomised, double-blind study to receive daily treatment with lozenges containing either L. brevis CD2 or placebo. Anticancer therapy was RT 70 Grays/35 fractions over 7 weeks with weekly Inj. Cisplatin 40 mg/m2. The study treatment was given during, and for 1 week after completion of anticancer therapy. Primary end-points were the incidence of grade III and IV oral mucositis and the percentage of patients able to complete anticancer treatment.

Findings

The efficacy analysis included the 188 patients who received ⩾1 week of study treatment. Grade III and IV mucositis developed in 52% of patients in the L. brevis CD2 arm and 77% in the placebo arm (P < 0.001). Anticancer treatment completion rates were 92% in the L. brevis CD2 arm and 70% in the placebo arm (P = 0.001). A larger proportion of patients remained free of mucositis when treated with L. brevis CD2 (28%) compared to the placebo (7%).

Interpretation

L. brevis CD2 lozenges reduced the incidence of grade III and IV anticancer therapy-induced oral mucositis and were associated with a lower overall rate of mucositis and a higher rate of anticancer treatment completion.

Introduction

Chemotherapy and radiotherapy are widely used therapeutic interventions for head and neck squamous cell carcinoma (HNSCC), and are often associated with severe side-effects resulting in morbidity and mortality. Oral complications that arise with these therapies include mucositis, xerostomia, bacterial, fungal, or viral infection (particularly in neutropenic patients), dental caries, loss of taste, and osteoradionecrosis.1 Virtually all patients who receive chemo-radiotherapy (CRT) to the head and neck area develop oral complications and oral mucositis. Grade III and IV mucositis, the most distressing condition, is reported in 40–70% of patients receiving CRT.2, 3, 4, 5, 6

Mucositis is painful and may result in dose reductions, treatment delays, or treatment discontinuation, which in turn can affect the outcome of anticancer therapy.1 Furthermore, extensive mucositis may limit adequate nutritional intake and necessitate hospitalisation for parenteral nutrition and narcotic analgesics, increasing the cost of anticancer therapy and impairing the patient’s quality of life (QoL).

Management of oral mucositis generally involves good oral hygiene, systemic analgesics, and preventive care such as benzydamine. For haematopoietic stem cell transplantation, palifermin is recommended. Various topical agents such as antimicrobial mouth rinse, l-glutamine, mucosal coating agents, and prostaglandin E2 (dinoprostone) are used, but there is no unequivocal evidence that these agents have any significant effect on mucositis.7 Thus there is a strong need for well-designed, randomised, placebo-controlled trials in this population to evaluate the safety and efficacy of new agents.

In the normal microflora of the mouth, it is possible to isolate several thousand microbial species. Some of these bacteria have a rich array of enzymes, which enables them, through metabolic activities, to modify their surrounding environment. The report of a successful treatment of the symptoms associated to the gut mucositis with the probiotic preparation VSL#3 has focused the attention towards the benefits consequent to the process of microflora manipulation.8

In particular, the strain of Lactobacillus brevis, L. brevis CD2, produces high levels of arginine deiminase and sphingomyelinase.9 Eukaryotic human cells can convert arginine into nitric oxide and polyamines by the actions of nitric oxide synthase and arginase, respectively. Arginine deiminase of bacterial origin competes with nitric oxide synthase and converts arginine to ammonia and citrulline; downregulating its conversion to nitric oxide, leading to a reduction in the levels of some of the known inflammatory parameters (cytokines IL-1α, IL-6, IL-8, TNF-α, IFN-у, PGE2 and matrix metalloproteinases).10 Bacterial sphingomyelinase can hydrolyse the platelet activating factor (PAF),11 a potent inflammatory cytokine, known to be associated with oral mucositis in radiation therapy.12

Previously, small studies demonstrated the efficacy of L. brevis CD2 in the prevention of inflammation. One study showed that L. brevis CD2 had anti-inflammatory effects in periodontal disease.10 Lozenges containing L. brevis CD2 were also used in the treatment of oral ulcers in Behçet’s syndrome, with a significant decrease in oral ulcers after 1 and 2 weeks of therapy.13

In view of the characteristics and potential benefits of L. brevis CD2, the present study was undertaken to test the in vivo efficacy of these bacteria in patients with head and neck cancer who were likely to develop therapy-induced mucositis. The study evaluated the efficacy of L. brevis CD2 lozenges in preventing oral mucositis in patients receiving CRT for HNSCC.

Section snippets

Study design

This was a randomised, double-blind, single centre, placebo-controlled study. It was conducted at the Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi. The Principal Investigator and the study sponsor, CD Pharma India Pvt. Ltd., jointly designed the study.

Ethics

The study data were gathered and informed consent was obtained in accordance with the Declaration of Helsinki. Study conduct was approved by the Institute’s ethics committee. All patients were

Patient disposition

From January 2007 to February 2009, 210 patients were enrolled, of whom 10 were screen failures. An efficacy evaluable population was defined by exclusion of the 12 subjects (8 in the L. brevis CD2 arm and 4 in the placebo arm) who discontinued within 1 week of starting the study treatment. Patient disposition is displayed in Fig. 1.

Baseline characteristics

Patients’ baseline characteristics are summarised in Table 1. The treatment groups were well balanced with regard to age and distribution of sex, clinical stage of

Discussion

Oral mucositis is an important, noxious, common complication of cancer treatments such as chemotherapy and radiotherapy. It is usually the dose-limiting factor for treating HNSCC patients. In a large (n = 450) retrospective review of stage III or IV head and neck cancer patients undergoing radiation therapy, 83% developed mucositis. Significantly more patients with mucositis (59%) required unplanned delays/breaks in therapy than did those without mucositis (16%).16

Oral mucositis is a consequence

Funding

The drug and the placebo were supplied by CD Pharma India Pvt. Ltd.

Conflict of interest statement

None declared.

Acknowledgement

We sincerely and gratefully acknowledge the help received from Prof. D.M. Keefe, and Ms. Ambika J. Sachdeva for their valuable suggestions in editing the manuscript.

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    ☆☆

    Part of this was presented at ASCO annual meeting 2009 at Orlando, Florida as oral presentation: ‘A randomized double blind phase III study of efficacy of Lactobacillus brevis CD 2 lozenges in preventing radiation and chemotherapy induced mucositis in head and neck cancer patients. Sharma Atul, Rath GK, Chaudhary SP, Thakar A, Mohanti BK, Bahadur S, Sahu AR, Johar A, Dwari AD. J Clin Oncol 2009;27:15s [suppl; abstr 6008]’.

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