British Journal of Radiology (2006) 79, 608-613
© 2006 British Institute of Radiology
doi: 10.1259/bjr/55190439
Randomized phase II study of GM-CSF to reduce mucositis caused by accelerated radiotherapy of laryngeal cancer
J J McAleese, FRCR1,
K M Bishop, BSc, RGN2,
R A'Hern, PhD2 and
J M Henk, FRCR2
1 Belvoir Park Hospital, Hospital Road, Belfast BT8 8JR, 2 Head and Neck Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
Correspondence: Dr J J McAleese, 46 Onslow Gardens, Belfast BT6 0AQ, UK
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Abstract
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Acute mucositis is dose-limiting in many accelerated radiotherapy schedules for head and neck cancer. Cytokines may be one means of reducing the severity of mucositis. A study was designed to assess the effect of subcutaneous molgramostin (granulocyte-macrophage colony stimulating factor; GM-CSF) injections on acute radiation morbidity in patients undergoing accelerated radiotherapy for laryngeal cancer. A prospective, randomized, observer-blind, controlled trial was conducted in 29 patients who were to receive radical radiotherapy over 3 weeks for early stage laryngeal cancer. Patients were randomized to receive 150 µg (
2 µg kg–1) GM-CSF subcutaneously once daily for 14 days after the second week of radiotherapy, or no GM-CSF. Patients were assessed weekly for grade of mucositis, skin reactions and related parameters. The severity of mucositis was reduced in the GM-CSF arm (p<0.05). No other end-points reached statistical significance. Two patients failed to complete their courses of GM-CSF. Three developed influenza type symptoms and in one an allergic reaction was noted. There was no difference in tumour control rates. Subcutaneous GM-CSF reduced the severity of mucositis in patients undergoing accelerated radiotherapy. Injections were well tolerated. Further studies of cytokines are warranted, to assess the feasibility of increasing the total doses of accelerated radiotherapy given, with the aim of improving tumour cure rates.
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Introduction
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When head and neck cancers are treated with accelerated radiotherapy, acute normal tissue effects can be dose limiting, especially when concurrent chemotherapy is given. This is because severe mucositis can lead to consequential late damage [1]. Reduction of the severity of mucositis could permit dose escalation with an increased chance of tumour cure.
The pathogenesis of mucositis is death of the actively dividing cells of the mucosal epithelium. The first clinical signs usually appear on the 12th or 13th day of radiotherapy. Healing takes on average 3 weeks after conventionally fractionated radiotherapy, but is prolonged in cases of severe mucositis. Various methods have been tried to reduce mucosal damage. Antiseptic and anti-inflammatory mouthwashes have no effect in reducing the severity of mucositis [2, 3]. Overgrowth of yeasts and aerobic gram negative cocci has been demonstrated, but studies of the use of local antifungals and antibiotics have given conflicting results; some suggest a small benefit, while others are negative [4–6].
Another approach is the use of growth factors to stimulate repair and proliferation of surviving mucosal cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) influences the proliferation and differentiation of stem cells and regulates several functions in mature leukocytes, macrophages and dendritic cells of the submucosa and dermis [7, 8]. GM-CSF administered to patients suffering cuts and burns decreases the healing period significantly [9]. GM-CSF has been successfully used to promote healing of chemotherapy-induced mucositis [10, 11]. It is therefore appropriate to investigate the use of GM-CSF to reduce the severity and increase the rate of healing of mucositis in patients with head and neck cancer. Several studies carried out to date have used GM-CSF with conventionally fractionated radiotherapy [12, 13].
Accelerated radiotherapy is used routinely for a variety of sites and stages of head and neck cancer, one of which is early laryngeal cancer. A large multicentre trial compared short (3–4 weeks) and long (5–6 weeks) treatment times for radiotherapy of laryngeal carcinoma. The short times gave equal local control and less late morbidity [14]. Since then, a 3-week 16-fraction regimen has been adopted as standard at the Royal Marsden Hospital. The majority of patients treated with this regimen develop symptomatic mucositis; grade 2 is observed in most, and grade 3 in about 10%. This group of patients was therefore deemed to be especially suitable for a study of the effect of GM-CSF with accelerated radiotherapy.
A possible disadvantage of growth factors is risk of stimulation of cell division in tumour cells, leading to accelerated repopulation during radiotherapy and a reduced chance of tumour cure. In one study another cytokine, G-CSF, was associated with reduced tumour control [15] when given from days 15 to 19 of a 38-day course of radiotherapy, i.e. during the first half of the course. We decided to try the effect of GM-CSF daily for 2 weeks starting on day 14 of a 21-day course of radiotherapy. Accordingly, the drug was not given until two-thirds of the radiation dose had been accumulated, so that the risk of accelerated repopulation should be minimized.
The optimal dose of GM-CSF is not known. The dose most often used to treat oral mucositis is 4 µg kg–1, but other studies suggest 1 µg kg–1 may be effective [13, 16]. Commercially available vials of GM-CSF contain 150 µg, sufficient for a dose of 2 µg kg–1 for most patients, so this latter dose was chosen for our study.
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Materials and methods
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Study design
The study was a prospective, randomized, observer-blind phase II trial. Approval was granted by the Royal Marsden Ethics Committee. Patients treated by radiotherapy for early glottic carcinoma were randomly allocated to receive or not daily injections of GM-CSF for 2 weeks, beginning on day 15 of the course of radiotherapy. A placebo injection was not used because it was not considered ethically justifiable. Accordingly, assessments of radiation effects were made and recorded by a blinded observer.
Eligibility criteria
Patients were eligible for the study if they had histologically proven T1 N0 or T2 N0 glottic carcinoma and were to be treated with radiotherapy using a 16-fraction 3-week regimen. They were required to be of WHO (World Health Organization) performance status grade 0 or 1. Patients were excluded if they had evidence of renal or hepatic impairment, serious infections requiring antibiotic therapy, were taking or likely to need corticosteroids, or were known to be allergic to GM-CSF.
Radiotherapy
External beam radiotherapy was given with a linear accelerator using 6 MV photons. The technique was to use lateral parallel-opposed fields, except in patients with a short neck, in whom anterior oblique fields with wedge filters were used. In most cases the fields were 5 cm square centred on the vocal cord, but in T2 cases the fields were extended by up to 2 cm either above or below the vocal cord to cover supraglottic or subglottic extension, respectively. All doses were prescribed at the ICRU intersection point. Once-daily fractions of 3.125 Gy were delivered to a total dose of 50 Gy in 16 fractions in 21 days.
GM-CSF
GM-CSF was administered at a dose of 150 µg by subcutaneous injection once daily for 14 days, beginning at the end of the second week of radiotherapy. It was therefore given during the final week of radiotherapy, and for 1 week after the end of radiotherapy.
Patients
All patients meeting the eligibility criteria treated at the Royal Marsden Hospital between September 1997 and October 2000 were offered entry to the study. 29 agreed to enter, and were randomly assigned to the active or control arms. The characteristics of the two groups are compared in Table 1
. There was an imbalance in stage distribution, with more T2 patients in the GM-CSF arm. Consequently more of this group were treated with larger fields. The mean field sizes were 32.7 cm2 in the GM-CSF group and 30.6 cm2 in the control group. The two groups were well balanced for all other variables.
Assessment and follow-up
Patients were seen weekly during treatment and for 3 weeks after treatment or until acute reactions settled. At each visit one of two independent observers, blinded to group allocation, scored mucositis by the Radiation Therapy Oncology Group (RTOG) system reproduced in Table 2 [17] using indirect laryngoscopy or flexible nasendoscopy to provide adequate visualization; data on skin erythema, moist and dry desquamation (as % of treatment field), pain on swallowing, severity of dysphagia, analgesic usage, evidence of candida infection and laryngeal oedema were collected at each visit. Weight was measured before starting and 2 weeks after the end of radiotherapy.
Statistical methods
It was anticipated that 60% of patients receiving the 3 week course of radiotherapy would develop one of the more severe grades of mucositis. We decided that in order for the routine use of GM-CSF to be worthwhile, this figure needed to be reduced to 10%. In order to demonstrate this difference at 90% power and 5% significance, 17 patients in each group would be needed. Accordingly, the intention was to recruit 34 patients to the study. Data were analysed on an intention to treat basis. A ranking method (Mann Whitney U-test) was chosen to analyse mucositis scores, as the grading system employed uses an ordinal scale. Patients were ranked on the basis of the frequency of maximal mucositis score over the study period. The other data were also analysed by non-parametric methods. Local control, disease-free survival and overall survival rates were computed by the Kaplan-Meier method and analysed by the log-rank method.
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Results
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Recruitment to the study proved to be disappointingly slow. There was a high refusal rate, because many patients were unwilling to receive a course of injections for a possible benefit only in terms of the side-effects of treatment. Eventually the study was terminated when 29 patients had been randomized.
15 patients were allocated to the GM-CSF treatment arm. Two patients failed to complete their prescribed course of injections. One patient discontinued after his second injection because of influenza-like symptoms. The second patient was admitted to a local hospital because of a chest infection and had his GM-CSF discontinued. All 29 patients completed their radiotherapy course as planned.
Figures 1 and 2 show the proportions of patients in each group with each grade of mucositis at each week after starting radiotherapy. The overall areas of the graphs are similar, but the arms differ in the relative contributions of each grade. The number of patients in the GM-CSF arm with maximum mucositis scores of grade 0, I, II and III were 1, 4, 10 and 0, respectively. The corresponding numbers for the control arm were 1, 0, 12 and 1, respectively. There were a greater proportion of maximum grade I scores in the GM-CSF arm compared with the control arm (27% vs 0%) but decreased grade II scores (67% vs 86%), and the only patient with a grade III score was in the control arm. The difference between the mucositis grades of the two groups was significant (ranking by Mann Whitney U = 56.5, p<0.05) The mean time to healing of mucositis in the GM-CSF group was approximately 60% that of the control arm, but this did not reach significance on the log rank test (p = 0.25).
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Figure 2. Proportion of patients with mucositis grades for granulocyte-macrophage colony stimulating factor (GM-CSF) arm.
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Figure 3. Allergic reaction at granulocyte-macrophage colony stimulating factor (GM-CSF) injection sites.
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One patient in the control arm required tube feeding. Otherwise, no patients had dysphagia at grade 3 (fluids only) or greater at 5 weeks. No differences were detected in dysphagia, odynophagia, analgesic usage, candida infection or laryngeal oedema. There was a difference noted in the average erythema grade in favour of the GM-CSF group (0.83 vs 1.33, p<0.05). No difference in moist desquamation or dry desquamation was noted. No statistically significant difference in weight change was noted between the groups.
Side effects of GM-CSF
12 patients who received GM-CSF had elevated white cell counts (WCC). The range of maximal WCC was 7.2–30.5 (median 19.7). All WCC had returned to normal within 3 weeks of completing injections (median 2 weeks). Three patients developed influenza-like symptoms with the GM-CSF and in one patient the injections were stopped because of this symptom. One patient developed an erythematous rash at his injection sites after completing his course of 14 injections (Figure 3
). He had a past history of allergy to radiographic contrast medium.
Tumour outcomes
The median follow-up is 28 months (range 6–45 months) during which time there have been three relapses in the control arm. One occurred at the primary site at 36 months and was successfully salvaged with laryngectomy. The other two patients had cervical node metastases, one at 10 months post-radiotherapy, the other at 13 months, and both underwent successful neck dissection. One patient in the GM-CSF arm developed a local recurrence and required a salvage laryngectomy at 12 months post-treatment. One patient in the GM-CSF group died of a myocardial infarction 5 months after his radiotherapy. The study is too small to draw conclusions about relative relapse rates, but there is no suggestion that GM-CSF adversely affected outcome.
Three patients in the control arm were diagnosed with a second malignancy. Two developed non-small cell lung cancer, one of which died within 3 months; the other received a course of radical radiotherapy. The third patient was diagnosed with small cell lung cancer and has received second line chemotherapy. One patient in the GM-CSF group developed a carcinoma of the rectum, which was treated with surgery alone.
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Discussion
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A meta-analysis of prophylactic GM-CSF in chemotherapy and radiotherapy induced mucositis [18] has shown a benefit with a relative risk of 0.51 (95% confidence intervals 0.29–0.91). Several studies have previously examined the ability of GM-CSF to modify radiation-induced mucositis (Table 3) but using differing radiotherapy regimens, doses of growth factor, and scoring systems for mucosal reactions. Five prospective randomized controlled trials of GM-CSF have been reported; in two, the agent was administered subcutaneously, and in the other three as a mouthwash.
Throuvalas et al [13] reported a randomized trial in 10 patients receiving conventionally fractionated radiotherapy. GM-CSF was administered subcutaneously at a dose of 1 µg kg–1 daily, beginning at the start of the third week of radiotherapy. The GM-CSF arm showed better pain control (p = 0.004) and less erythema (p = 0.09).
Makonnen et al [12] conducted a randomized controlled trial comparing subcutaneous GM-CSF 150–300 µg per day plus sucralfate mouthwash versus sucralfate mouthwash control, in 40 patients receiving either conventionally fractionated or hyperfractionated radiotherapy with break. GM-CSF was begun at the end of the first week of radiotherapy and continued throughout the course of treatment. No difference was found in degree or frequency of mucositis in the overall group or by type of fractionation. Skin reactions, fever and bone pain were the most common side effects in the GM-CSF arm.
Sprinzl et al [19] conducted a randomized control trial in 35 patients using GM-CSF mouthwash. All patients had advanced head and neck cancer and were treated with two cycles of radiotherapy (each 30 Gy in 15 fractions) and concomitant mitomycin C and 5FU chemotherapy. Data were collected during the first radiotherapy cycle. No differences in mucositis or oral pain were noted. Saarilathi et al [20] compared GM-CSF with sucralfate mouthwash in a randomized study in 40 patients with oral cancer receiving post-operative radiotherapy. Mucositis tended to be less severe and heal more quickly in the GM-CSF treated group (p = 0.07) and there were fewer requirements for opioid pain relief (p<0.05).
Two case-control studies of subcutaneous GM-CSF have been reported. Kannan et al [16] compared the results of 10 patients treated with 1 µg kg–1 body weight GM-CSF and conventionally fractionated radiotherapy with historic controls. None of the 10 patients developed grade III mucositis compared with 49% of controls. Itching in 20% and body aches in 40% were the main side effects, but both were successfully treated with simple oral medications. Wagner et al [21] compared the use of subcutaneous GM-CSF 5 µg kg–1 body weight in 16 patients receiving conventionally fractionated radiotherapy with historical controls. Pain relief was improved in the GM-CSF group (p = 0.011). A trend towards a decreased degree of mucositis was noted. Only mild reactions to GM-CSF were reported.
All of the above studies were too small to provide a conclusive result, but overall there is a trend towards a reduction in severity of radiation mucositis with GM-CSF. Our study also showed a reduction in the severity of mucositis experienced by patients receiving accelerated radiotherapy. This was despite an imbalance in the two arms so that more patients in the GM-CSF arm were treated with larger fields.
Side effects to GM-CSF seem to be generally mild. Kannan et al [16] reported itching in 20% and body aches in 40% of patients receiving the drug. Wagner et al [21] observed bone pain in 3% and pyrexia in 3%. Makonnen et al [12] reported local skin reaction in 13%, fever in 6% and bone pain in 5%. In our study, 20% had myalgia/flu-like symptoms and one patient had an allergic reaction. Subcutaneous GM-CSF therefore appears to be well tolerated.
Maurer-Schulze et al [22] suggest that low doses of GM-CSF stimulate cell proliferation in human tumour xenografts in nude mice, but inhibit proliferation at higher doses. The data in Makonnen's paper [12] show a non-significant trend for decreased survival in the GM-CSF arm. Because of the possible potential for accelerating tumour cell re-population [23, 24], GM-CSF was not administered until the final week of radiotherapy in our study. We did not observe a difference in local control, but larger studies would be needed to confirm this finding.
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Conclusions
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GM-CSF was well tolerated and no decrease in local control was seen. A decrease in severity of mucositis, consistent with the biological actions of GM-CSF as a promoter of wound healing, has been shown. GM-CSF appears promising as a potential modifier of radiotherapy-induced mucositis, but larger studies are required to establish its value. More specific growth factors are now under investigation: for example, Dörr and colleagues have demonstrated a radio-protective effect of keratinocyte growth factor on mouse oral mucosa [25]. Cytokines are a promising method of improving therapeutic ratio in radiotherapy of head and neck cancer, especially with accelerated regimes in which acute normal tissue effects are dose-limiting.
Received for publication March 8, 2005.
Revision received September 9, 2005.
Accepted for publication September 16, 2005.
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Abstract
Introduction
