Therapeutic effect of recombinant human epidermal growth factor (rhEGF) on mucositis in patients undergoing radiotherapy,with or without chemotherapy,for head and neck cancer

BACKGROUND:

We evaluated the efficacy of topically applied human recombinant epidermal growth factor (rhEGF) for the treatment of oral mucositis induced by radiotherapy (RT), with or without chemotherapy, in patients with head and neck cancer.

METHODS:

Patients receiving definitive chemoradiotherapy, definitive RT, or postoperative RT to the oral cavity or oropharynx were recruited from 6 institutions and enrolled in a randomized, double‐blind, placebo‐controlled phase 2 trial. Patients were assigned to a placebo group or to 1 of 3 EGF‐treatment groups (10, 50, or 100 μg/mL doses, delivered in a spray, twice daily). The grade of mucositis was evaluated using the Radiation Therapy Oncology Group (RTOG) scoring criteria. Responders to EGF were defined as having an RTOG grade of 2 or lower at the fourth‐ or fifth‐week examinations during RT, but an enduring RTOG grade 2 for 2 weeks was an exception.

RESULTS:

Of the 113 patients included in the study, 28 received placebo and 29 received EGF at 10 μg/mL, 29 at 50 μg/mL, and 27 at 100 μg/mL. EGF significantly reduced the incidence of severe oral mucositis at the primary endpoint (a 64% response was observed with 50 μg/mL EGF vs a 37% response in the control group; P = .0246).

CONCLUSIONS:

The EGF oral spray may have potential benefit for oral mucositis in patients undergoing RT for head and neck cancer. Phase 3 studies are ongoing to confirm these results. Cancer 2009. © 2009 American Cancer Society.     

Carbogen breathing combined with radical radiotherapy in advanced head and neck cancer patients with severe co-morbidities

AimsTo assess the feasibility of carbogen breathing combined with radical radiotherapy in patients with advanced head and neck cancer who are unfit to receive concomitant chemotherapy.Materials and methodsTwenty patients (median age 66 years) with advanced squamous cell carcinoma of the head and neck were treated with either concomitant boost radiotherapy (75%) or mono-fractionated radiotherapy (25%) combined with carbogen breathing. The median tumour dose was 69.5 Gy. The main sites of disease were the oropharynx in 50%, the oral cavity in 15% and the hypopharynx in 30%. All but one patient had stage III (25%) or IV (70%) disease. The median follow-up for the surviving patients was 26 months (range 6–50 months).ResultsCarbogen breathing was well tolerated, permitting its delivery throughout the radiotherapy course. Three patients had treatment interruption because of acute toxicities (median 15 days; range 3–30 days). Grade 3 Radiation Therapy Oncology Group acute toxicity was observed in 80% of the patients (mainly mucositis), and nutritional support was required in eight patients (40%). Grade 2 late toxicity occurred in 30%; one patient presented with grade 4 late toxicity (bone necrosis). The 2-year actuarial locoregional control for all patients and for those treated with accelerated radiotherapy was 56% and 67%, respectively. The corresponding rates for disease-free survival were 45% and 53%.ConclusionsConsidering the poor results of radiotherapy alone in advanced head and neck cancer, these results suggest that carbogen breathing may be a valid alternative for patients with severe co-morbidities who are unfit to receive concomitant chemotherapy.     

Comparison of radiation-induced oral mucositis scoring systems

BACKGROUND: A number of oral toxicity scoring systems have been described, but their direct comparison has rarely been undertaken and little data exists. An impediment to mucositis research has been the lack of an accepted, validated scoring system. The objective of this study was to design a test and validation of scoring systems. MATERIALS AND METHODS: Forty-three patients with head and neck malignancies who had been irradiated were evaluated. Five different mucositis scoring systems (World Health Organization, Radiation Therapy Oncology Group, "Hickey", "Van der Schueren" and "Makkonen") were compared with each other. RESULTS: Daily mucositis scores demonstrated a high correlation among scoring systems (P < 0.05 and coefficient of correlation kappa and r = 0.5-0.95). Objective mucositis scores demonstrated a strong correlation with symptoms. CONCLUSIONS: All scoring systems were equally valid. The exact grading of mucositis is achieved by combining clinical information about pain and nutritional status with oral mucosal reactions.     

金因肽在头颈部肿瘤患者放射治疗中的临床应用观察

目的评价金因肽在头颈部肿瘤患者放射治疗中的临床作用。方法将52例头颈部肿瘤放射治疗患者随机分为治疗组和对照组,每组各26例。治疗组患者给予放射治疗＋漱口液＋金因肽口腔喷雾,对照组患者为放射治疗＋漱口液。结果急性口腔黏膜炎反应程度在放射治疗第5周、7周末时差异有统计学意义;在放射治疗结束时,两组患者贫血及体重下降〉2．5kg的患者比例差异有统计学意义。结论在头颈部肿瘤患者放射治疗时使用金因肽口腔喷雾,不仅可以降低急性口腔黏膜炎的发生率及反应级别,而且可以间接降低贫血发生及维持患者的体重,有利于放射治疗顺利进行及保证疗效。     

End Stage Palliative Care of Head and Neck Cancer: a Case Study

Background: Locally advanced head and neck cancer is generally incurable and has a short survival rate. Thisstudy aimed to evaluate symptom relief, disease response, and acute toxicity after palliative hypo-fractionatedradiotherapy and long-term survival in affected patients. Materials and Methods: Between January 2011 toDecember 2011, 80 patients who were histopathologically diagnosed as having stage III or stage IV head andneck squamous cell carcinoma based on Eastern Cooperative Oncology Group (ECOG) performance status 1-3,were offered palliative radiotherapy (20 Gy/5Fr/5 Days). Later these patients were evaluated on 30th day aftercompletion of treatment for disease response based on World Health Organisation (WHO) criteria and palliationof symptoms using symptomatic response grading and acute toxicities by the Radiation Therapy Oncology Group(RTOG). Many patients were given post radiation therapy (RT) palliative chemotherapy for appropriate palliativecare and a few patients were selected for further curative RT. The overall survival was also evaluated amongthis group of patients with last follow up date of 1st May, 2014. Results: The most common presenting complaintwas pain followed by dysphagia. Most patients (60-70%) had appreciable relief in their presenting symptoms. Agood response was observed in the majority following palliative RT; a few patients had progressive disease andsome had stable and regressed disease. None of the patients experienced radiation toxicity that required hospitaladmission. Almost all showed grade one and two acute skin and mucosal toxicity one month after completion oftreatment. The mean survival days for patients given only hypofractionated palliative RT was 307 days, thosewith post palliative RT and palliative chemotherapy was 390 days and patients who went on to receive furtherpalliative RT and curative RT dose had significantly overall survival of 582 days. Conclusions: Advanced headand neck cancer should be identified for suitable palliative hypofractionated radiotherapy to achieve acceptablesymptom relief in a great proportion of patients and should be followed by palliative chemotherapy or curativeRT in suitable cases for long-term symptom-free survival.     

Use of topical misoprostol to reduce radiation‐induced mucositis: Results of a randomized,double‐blind,placebo‐controlled trial

Radiation‐induced mucositis is an acute reaction of the mucosa of patients undergoing head and neck radiotherapy. It can have debilitating and dose‐limiting consequences. There is no consensus on an accepted intervention that significantly reduces its severity. Misoprostol is a synthetic prostaglandin E₁ analogue, with properties of a mucosal cytoprotectant. We designed a randomized, double‐blind, placebo‐controlled trial of misoprostol in patients with head and neck cancer. The aim of this study was to determine if topical misoprostol was effective in reducing the severity of radiation‐induced mucositis in patients receiving radical dose radiotherapy. The effect of this intervention on a patient’s general well‐being was also investigated. The primary end‐point of the study was the incidence of Radiation Therapy Oncology Group grade 3 mucositis. Between 1999 and 2002, 83 patients were recruited into the study at Westmead and Nepean Hospitals, Sydney. Forty‐two patients were randomized to receive misoprostol and 41 to receive a placebo. Most patients received radiotherapy in the adjuvant setting (52 of the 83) and had either an oral cavity (42 of the 83) or an oropharyngeal (16 of the 83) cancer. We could not identify any significant difference in the incidence of severe mucositis based on whether patients were allocated to receive misoprostol or placebo. There was no significant difference in the mean area under the mucositis curve (13.2 vs 16.6; P = 0.1). Patients allocated to misoprostol did report slightly increased soreness (7.6 vs 6.9; P = 0.04) and a greater use of analgesics. However, this difference did not translate into a worse feeling of general well‐being as measured by a simple visual analogue scale (5.8 vs 5.2; P = 0.3). In conclusion, we were unable to identify a reduction in radiation‐induced mucositis in patients receiving misoprostol. There is a paucity of high‐level evidence on potentially useful interventions and a continued need for new and innovative research, incorporating quality‐of‐life measurements, in patients experiencing radiation‐induced mucositis.     

Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034.

To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region, a randomized clinical trial was conducted under the auspices of the Head and Neck Intergroup (Radiation Therapy Oncology Group, Southwest Oncology Group, Eastern Oncology Group, Cancer and Leukemia Group B, Northern California Oncology Group, and Southeast Group). Eligible patients had completely resected tumors of the oral cavity, oropharynx, hypopharynx, or larynx. They were then randomized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy (CT/RT) or postoperative radiotherapy alone (RT). Patients were categorized as having either "low-risk" or "high-risk" treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm, there was extracapsular nodal extension, and/or there was carcinoma-in-situ at the surgical margins. Radiation doses of 50-54 Gy were given to "low-risk" volumes and 60 Gy were given to "high-risk" volumes. A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis. The 4-year actuarial survival rate was 44% on the RT arm and 48% on the CT/RT arm (p = n.s.). Disease-free survival at 4 years was 38% on the RT arm compared to 46% on the CT/RT arm (p = n.s.). At 4 years the local/regional failure rate was 29% vs. 26% for the RT and CT/RT arms, respectively (p = n.s.). The incidence of first failure in the neck nodes was 10% on the RT arm compared to 5% on the CT/RT arm (p = 0.03 without adjusting for multiple testing) and the overall incidence of distant metastases was 23% on the RT arm compared to 15% on the CT/RT arm (p = 0.03). Treatment related toxicity is discussed in detail, but, in general, the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy. Implications for future clinical trials are discussed.     

Zinc sulfate in the prevention of radiation-induced oropharyngeal mucositis: a prospective, placebo-controlled, randomized study

PURPOSE: To determine the effect of oral zinc sulphate supplementation on radiation-induced oropharyngeal mucositis in patients with head-and-neck cancer. MATERIALS AND METHODS: Thirty patients with head-and-neck cancer were randomly assigned to receive either zinc sulfate or placebo. Primary tumors were localized in the larynx in 14 patients, in the nasopharynx in 4, in the oral cavity in 4, in a salivary gland in 1, in the maxillary sinus in 1, in neck nodes (lymphoma presenting primarily) in 3 and in neck metastases from an unknown primary in 3. In the placebo group, 3 patients were excluded; 1 patient died during treatment, 1 left the study, and 1 did not come to the 6 week control visit. The patients were treated with telecobalt radiotherapy at conventional fractionation (2 Gy/fraction, five fractions weekly, for 20-35 fractions within 4-7 weeks). The median radiation dose was 6400 cGy (4000-7000 cGy). Oral mucositis was assessed by two independent physicians, experts in radiation oncology, using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring criteria. RESULTS: In the zinc sulfate group, Grade 3-4 mucositis was not detected in any patient; Grade 0 mucositis was detected in 2, and Grade 1 in 8, and Grade 2 in 5 patients. In the placebo group, Grade 2 mucositis was detected in 4 and Grade 3 in 8 patients. We observed that the degree of mucositis in the patients in the zinc sulfate group was significantly lower than that in the placebo group (p < 0.05). Confluent mucositis developed earlier in the placebo group than in the zinc sulfate group after the onset of treatment (p < 0.05) and started to improve sooner in the zinc sulfate group than in the placebo group (p < 0.05). CONCLUSIONS: Zinc sulfate is beneficial in decreasing the severity of radiation-induced mucositis and oral discomfort. These results should be confirmed by additional evaluation in randomized studies with a larger number of patients.     

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

PurposeRadiation 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 MaterialsAn 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.ResultsA 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).ConclusionsProphylactic administration of FCZ twice weekly during CRT for head-and-neck cancer reduces incidence of mucositis and thrush.     

Effect of pilocarpine during radiation therapy: results of RTOG 97-09, a phase III randomized study in head and neck cancer patients

Radiation therapy is an important curative modality in the treatment of patients with head and neck cancer. However, radiation-induced changes in the oral cavity, such as xerostomia and mucositis, are among the most debilitating treatment sequelae experienced by patients undergoing radiation therapy, and attempts at ameliorating these side effects have been poor at best. Pilocarpine has been approved for post-radiation xerostomia, and the effect of its use during radiation therapy on salivary flow, xerostomia, mucositis, and quality of life (QOL) was assessed in a phase III study conducted by the Radiation Therapy Oncology Group (RTOG 97-09). In total, 245 evaluable patients were randomized to pilocarpine or placebo. Selected patients were required to have > or = 50% of the volume of the major salivary glands receive > or = 50Gy; to agree to provide stimulated and unstimulated samples of saliva (measured in g) before treatment, at the end of treatment, and 3 and 6 months after completion of radiation therapy; and to complete the University of Washington Head and Neck Symptom Scale. Following the completion of radiation therapy, the average unstimulated salivary flow was statistically greater in the pilocarpine group, whereas no difference was noted following parotid stimulation. There was no effect on the amelioration of mucositis. The results of the QOL scales did not reveal any significant difference between the pilocarpine and placebo groups with regard to xerostomia and mucositis. The significant difference in unstimulated salivary flow supports the concomitant use of oral pilocarpine to decrease radiation-associated xerostomia. However, the absent correlation between improved salivary flow and QOL scores is of some concern (though not a new finding) and may be related to the existence of comorbidities and the lack of effect on mucositis.     

Advanced olfactory neuroblastoma treated with combined conventional and hypofractionated stereotactic radiotherapy

Three patients with olfactory neuroblastoma (ONB) of the nasal and/or paranasal cavity were treated with a combination of conventional radiotherapy (RT) and hypofractionated stereotactic radiation therapy (SRT). Radiation doses of 30 to 50 Gy were delivered in 12 to 25 fractions using conventional RT, and then an additional 20 to 25 Gy was delivered in 5 fractions using SRT. Follow-up time was 42, 53, 65 months, three patients were alive, and local control was obtained in all, complete response (CR) in 2 and partial response (PR) in 1. Two patients had recurrence out of the radiation field and received salvage therapy. According to the Radiation Therapy Oncology Group (RTOG) acute/late radiation morbidity scoring criteria, there were no adverse effects of grade 3 or higher. The combined treatment with conventional RT and hypofractionated SRT achieved excellent local control without serious adverse effects.     

重离子束（12C^6＋）治疗头颈部浅表肿瘤疗效观察

目的：观察采用重离子研究装置（HIRFL）引出重离子束治疗头颈部浅表肿瘤的近期疗效和急性不良反应。方法：自2007年1月至2010年10月,我院13例头颈部浅表肿瘤患者采用能量为80MeV／u～100MeV／u的碳离子（他C6＋）束进行重离子束放射治疗。总剂量46GyE-70GyE,1次／天,连续12天。应用RTOG急性放射损伤分级标准判断不良反应,应用WHO疗效标准评价近期疗效。结果：非恶黑性皮肤癌、乳头状瘤、恶性黑色素瘤有效率（CR＋PR）分别为100％（9／9）、50％（1／2）和50％（1／2）,13例患者总局部控制率为85％（11／13）。皮肤不良反应发生率1、2、3度分别为30．8％（4／13）,15．4％（2／13）,15．4％（2／13）,未观察到4级皮肤不良反应。结论：重离子束放射治疗头颈部浅表肿瘤有较好的近期疗效,不良反应轻微,患者可耐受。     

Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3)

PURPOSE: Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G(1) phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT. METHODS AND MATERIALS: A total of 216 patients were randomized to morning (8-10 AM) vs. afternoon (4-6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system. RESULTS: Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66-70 Gy in 33-35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025). CONCLUSION: In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving >/=66 Gy and in patients who smoked during therapy.     

Concurrent Chemoradiation with Weekly Cisplatin for the Treatment of Head and Neck Cancers: an Institutional Study on Acute Toxicity and Response to Treatment

Background: Concurrent chemoradiation with three weekly high dose cisplatin is the non-surgical standard ofcare for the treatment of locally advanced head and neck cancers. Although this treatment regime is efficacious,it has high acute toxicity, which leads not only to increased treatment cost, but also to increased overall treatmenttime. Hence, the current study was undertaken to evaluate the acute toxicity and tumor response in head andneck cancer patients treated with concurrent chemoradiation using 40 mg/m2 weekly cisplatin, which has beenour institutional practice. Materials and Methods: This single institution retrospective study included data for287 head and neck cancer patients treated with concurrent chemoradiation from 2012 to 2014. Results: Themean age of the patients was 48.8 years. The most common site of involvement was oral cavity. Most of the studypatients presented with advanced stage disease. The mean overall treatment time was 56.9 days. Some 67.2%had overall complete response to treatment as documented till 90 days from the start of treatment. Accordingto the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria, mucositis wasseen in 95.1% of the patients. Dermatitis and emesis were observed in 81.9% and 98.6%, respectively. Regardinghaematological toxicity, 48.8% and 29.6% suffered from anaemia and leukopenia, respectively, during treatment.Acute kidney injury was assessed using the Common Terminology Criteria for Adverse Events (CTCAE), andwas found in 18.8% of the patients. Conclusions: Concurrent chemoradiotherapy with weekly cisplatin is aneffective treatment regime for head and neck cancers with reasonable toxicity which can be used in developingcountries, where cost of treatment is so important.     

The impact of concurrent granulocyte macrophage-colony stimulating factor on radiation-induced mucositis in head and neck cancer patients: a double-blind placebo-controlled prospective phase III study by Radiation Therapy Oncology Group 9901

PURPOSE: Based on early clinical evidence of potential mucosal protection by granulocyte-macrophage colony stimulating factor (GM-CSF), the Radiation Therapy Oncology Group conducted a double-blind, placebo-controlled, randomized study to test the efficacy and safety of GM-CSF in reducing the severity and duration of mucosal injury and pain (mucositis) associated with curative radiotherapy (RT) in head-and-neck cancer patients. METHODS AND MATERIALS: Eligible patients included those with head-and-neck cancer with radiation ports encompassing >50% of oral cavity and/or oropharynx. Standard RT ports were used to cover the primary tumor and regional lymphatics at risk in standard fractionation to 60-70 Gy. Concurrent cisplatin chemotherapy was allowed. Patients were randomized to receive subcutaneous injection of GM-CSF 250 microg/m2 or placebo 3 times a week. Mucosal reaction was assessed during the course of RT using the National Cancer Institute Common Toxicity Criteria and the protocol-specific scoring system. RESULTS: Between October 2000 and September 2002, 130 patients from 36 institutions were accrued. Nine patients (7%) were excluded from the analysis, 3 as a result of drug unavailability. More than 80% of the patients participated in the quality-of-life endpoint of this study. The GM-CSF did not cause any increase in toxicity compared with placebo. There was no statistically significant difference in the average mean mucositis score in the GM-CSF and placebo arms by a t test (p = 0.4006). CONCLUSION: This placebo-controlled, randomized study demonstrated no significant effect of GM-CSF given concurrently compared with placebo in reducing the severity or duration of RT-induced mucositis in patients undergoing definitive RT for head-and-neck cancer.     

Benzydamine for prophylaxis of radiation-induced oral mucositis in head and neck cancers: a double-blind placebo-controlled randomized clinical trial

We evaluated the efficacy of benzydamine oral rinse for prevention of radiation-induced mucositis. Patients with head and neck cancers, who were referred in 2004–2005, received an oral rinse of either benzydamine or placebo. One hundred patients were randomized in this trial. At the end of the study, 19 patients were excluded from the analysis because they did not use the medication for the assigned period. In the benzydamine group, the frequency of mucositis grade ≥3 was 43.6% in contrast to 78.6% in other group ( P  = 0.001). Grade ≥3 mucositis was 2.6 times more frequent in the placebo group. Intensity of mucositis increased up to fourth week of treatment in both groups to grade 2. In the treated group the grade of mucositis was approximately constant to the end of therapy; but in the control group it raised to grade 3 ( P  < 0.001). The highest grade of mucositis during the treatment time was significantly different between two groups ( P  = 0.049). The median interval to observation of grade ≥2 mucositis was 24 days in the placebo group and 28 days in the benzydamine group ( P  = 0.12). Benzydamine oral rinse seems to be effective, safe, and well tolerated for prophylactic treatment of radiation-induced oral mucositis in head and neck tumours.     

Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life

BACKGROUND.

The risk, severity, and patient‐reported outcomes of radiation‐induced mucositis among head and neck cancer patients were prospectively estimated.

METHODS.

A validated, patient‐reported questionnaire (OMDQ), the FACT quality of life (QOL), and the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scales were used to measure mucositis (reported as mouth and throat soreness), daily functioning, and use of analgesics. Patients were studied before radiotherapy (RT), daily during RT, and for 4 weeks after RT.

RESULTS.

Contrary to previous reports, the risk of mucositis was virtually identical in the 126 patients with oral cavity or oropharynx tumors (99% overall; 85% grade 3‐4) compared with 65 patients with tumors of the larynx or hypopharynx (98% overall; 77% grade 3‐4). The mean QOL score decreased significantly during RT, from 85.1 at baseline to 69.0 at Week 6, corresponding with the peak of mucositis severity. The mean functional status score decreased by 33% from 18.3 at baseline to 12.3 at Week 6. The impact of mucositis on QOL was proportional to its severity, although even a score of 1 or 2 (mild or moderate) was associated with a significant reduction in QOL (from 93.6 at baseline to 74.7 at Week 6). Despite increases in analgesic use from 34% at baseline to 80% at Week 6, mean mucositis scores exceeded 2.5 at Week 6.

CONCLUSIONS.

Mucositis occurs among virtually all patients who are undergoing radiation treatment of head and neck cancers. The detrimental effects on QOL and functional status are significant, and opioid analgesia provides inadequate relief. Preventive rather than symptom palliation measures are needed. Cancer 2008. © 2008 American Cancer Society.     

Phase II clinical trial of local use of GM-CSF for prevention and treatment of chemotherapy- and concomitant chemoradiotherapy-induced severe oral mucositis in advanced head and neck cancer patients: an evaluation of effectiveness,safety and costs

In the present open non-randomized phase II study we looked for effectiveness, safety, tolerability and costs of locally applied GM-CSF in preventing or treating mucositis in patients receiving chemotherapy or chemoradiotherapy for head and neck cancer. In addition to clinical mucositis scoring system, the effects of treatment with GM-CSF were evaluated by its impact on patient quality of life and by laboratory immunological assays such as serum proinflammatory cytokines, IL-2 and leptin. The trial was designed to assess the effectiveness of local GM-CSF treatment in two different settings: i) prophylaxis of mucositis; ii) treatment of mucositis. Prophylaxis was chosen for chemoradiotherapy treatments of high mucosatoxic potential, while curative treatment was reserved for chemotherapy or chemoradiotherapy treatments of lesser potential of inducing mucositis. From January 1998 to December 2001, 68 patients entered the study. The great majority of patients of both groups had head and neck cancer, were stage IV, PS ECOG 0-1, were habitual smokers and were treated with chemotherapy and concomitant (or sequential) chemoradiotherapy. Forty-six patients were included in the 'prophylactic' setting and 22 patients in the 'curative' setting. The main findings of our study are: only 50% of patients included in the 'prophylactic' setting developed mucositis; the duration of oral mucositis from appearance until complete remission was significantly shorter in the 'prophylactic' than in the 'curative' setting; the mean grade of oral mucositis at baseline, on day 3 of therapy and on day 6 of therapy was significantly lower in the 'prophylactic' than in the 'curative' setting; 24 (55.82%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis at baseline compared to 25 (80.60%) patients in the 'curative' setting (p=0.048). Thirteen (30.23%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis on day 3 of therapy compared to 19 (61.29%) patients in the 'curative' setting (p=0.015); 'prophylactic' setting was able to shorten grade 3/4 oral mucositis to grade 0/1 more effectively than the 'curative' one on day 6 of therapy (p=0.05). The present clinical trial is to date by far the largest study assessing the effectiveness of topical GM-CSF and it is the first study comparing the efficacy of topical GM-CSF in the 'prophylactic' setting, i.e., with the aim to prevent the chemoradiotherapy-induced oral mucositis, with that in the 'curative' treatment, i.e., the therapy for established oral mucositis. The topical application of GM-CSF was demonstrated to be effective for oral mucositis induced by chemotherapy and chemoradiotherapy regimens. Moreover, the 'prophylactic' setting was demonstrated to be more effective than the 'curative' one.     

A Phase III placebo-controlled trial of oral pilocarpine in patients undergoing radiotherapy for head-and-neck cancer

PURPOSE: To test the hypothesis that the use of oral pilocarpine during and after radiotherapy (RT) for head-and-neck cancer would reduce the symptoms of post-RT xerostomia. METHODS AND MATERIALS: One hundred thirty patients were randomized in a double-blind method to receive either pilocarpine (5-mg tablets) or placebo three times daily starting on Day 1 of RT and continuing for 1 month after treatment. The eligibility criteria included a planned dose of >50 Gy as radical or postoperative RT for head-and-neck cancer, with at least 50% of both parotid glands included in the treatment fields. The primary outcome measure was the severity of xerostomia as assessed by a patient-completed linear analog scale 3 months after RT. Secondary outcome measures included quality of life during therapy (as assessed by the McMaster University Head-and-Neck Questionnaire) and severity of mucositis during RT (as assessed using Radiation Therapy Oncology Group scales). RESULTS: No difference was observed between the pilocarpine-treated patients and the placebo group in the severity of xerostomia score as assessed by linear analog scale at baseline and 1, 3, and 6 months after treatment (repeated measures analysis, p = 0.92). No difference was apparent in the severity of mucositis during RT; 56.3% of patients receiving pilocarpine had Grade III/IV mucositis compared with 50.8% treated with placebo. No difference in quality of life was noted between the treatment groups during or after RT. The questionnaire score at 3 months after RT was 5.0 (SD 1.0). in the pilocarpine group and 4.9 (SD 0.9) in the placebo group. CONCLUSION: We were unable to detect a beneficial effect of pilocarpine on RT-induced xerostomia when administered during RT for head-and-neck cancer.     

Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study

In patients who have locally advanced and inoperable head and neck cancer, the achievement of initial local control (complete response) of the disease with initial definitive treatment with radiotherapy (RT) with or without chemotherapy, is an important prognostic factor for overall survival. Cisplatin 100 mg/M2-intravenously (IV) with hydration and mannitol diuresis was given every 3 weeks for three doses concurrently with definitive radiotherapy (followed by salvage surgery [if possible] for persistent disease) was activated by the Radiation Therapy Oncology Group (RTOG) in 1981. One hundred thirty-four patients were initially registered and 124 were eligible and analyzed for this report. Eighty-two percent of the patients had Stage IV disease and greater than 50% of the primary sites were in oropharynx (39%), nasopharynx (22%), and oral cavity (18%). Eighty-seven percent of the patients are known to have finished the planned RT greater than 6450 cGy and 60% received three courses of cisplatin. Overall, 60% finished the planned combined treatment. Complete response to initial treatment occurred in 69% and an additional one patient (1%) was rendered disease-free after radical node dissection. Severe toxicities were as follows: leukopenia, 11%; anemia, 8%; nausea and vomiting, 6%; stomatitis, 31%; and renal, 6%. One toxic death occurred when a nephrotoxic antibiotic was administered at the same time. All patients were evaluated for total disease and survival regardless of compliance to the treatment or the cause of death. At 1 year, an estimated 51% of the patients had their disease totally controlled and an estimated 66% were alive. Incidence of initial complete response by various patient characteristics also were analyzed. The authors concluded that the combination of cisplatin and radiotherapy is an effective and safe treatment in patients with advanced head and neck cancer and needs to be tested against radiotherapy alone.