Re-irradiation combined with capecitabine in locally recurrent squamous cell carcinoma of the head and neck

Background

We performed a prospective phase II trial to investigate the safety and efficacy of radiotherapy combined with capecitabine in patients suffering from a recurrence of a squamous cell carcinoma of the head and neck (SCCHN) within a previously irradiated field.

Patients and methods

A total of 31 evaluable patients with recurrent SCCHN received re-irradiation with a total dose of 50?Gy (25 fractions over 5?weeks) up to a maximum of 60?Gy combined with 900?mg/m²/day capecitabine given on the days of radiotherapy.

Results

The median time to relapse after the first course of radiotherapy was 15?months. The overall response rate in our study was 68% including 6?patients with a complete response. The median overall survival was 8.4?months. Grade 3 or 4 mucositis occurred in 4?patients and 1?patient, respectively. No grade 4 hematological toxicities were observed; 1?patient had grade 3 anemia. The cumulative median lifetime dose was 116?Gy.

Conclusion

Capecitabine combined with re-irradiation is a well-tolerated treatment in patients with recurrent SCCHN. In light of its good tolerability, it appears to be a potential option for patients with a reduced performance status and may also serve as a basis for novel treatment concepts, such as in combination with targeted therapies.     

Re-irradiation with interstitial pulsed-dose-rate brachytherapy for unresectable recurrent head and neck carcinoma

PurposeTo assess the long-term results of protocol-based interstitial pulsed-dose-rate (PDR) brachytherapy combined with simultaneous chemotherapy in selected patients with recurrent head and neck tumors not amenable to salvage surgery.Methods and MaterialsA total of 51 patients with recurrent head and neck cancer were treated with interstitial PDR brachytherapy. Forty patients (78%) had salvage brachytherapy alone using a median total dose of 60 Gy. Salvage brachytherapy in combination with external beam therapy was performed in 11 patients (22%) using a median total dose of D_REF = 27 Gy. Simultaneously with the PDR brachytherapy, a concomitant chemotherapy was administered in 35/51 (69%) of patients. The analysis was performed after a median followup of 58 months.ResultsLocal control rates calculated according to Kaplan–Meier after 2 and 5 years were 71% and 57%, respectively. Comparing results of salvage PDR brachytherapy with or without simultaneous chemotherapy, the 5-year local recurrence-free survival rates were 78.9% vs. 38.5% (p = 0.01), respectively. No other patient or treatment-related parameters had a significant influence on treatment results. A total of 9/51 (17.7%) and 6/51 (11.8%) patients developed soft-tissue necrosis or bone necrosis, respectively, but only 2% of patients required surgical treatment.ConclusionsPDR interstitial brachytherapy with pulse doses between 0.4 and 0.7 Gy/h/24 h with simultaneous chemotherapy is an effective and safe option for curative therapy in selected patients with head and neck cancer in previously irradiated areas, which are not suitable for salvage surgery.     

Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas

Aim

The goal of the present work was to compare outcomes of definitive concurrent cisplatin-based chemoradiotherapy (CRT) with cetuximab-based bioradiotherapy (BRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC).

Patients and methods

Between 2006 and 2012, 265 patients with locally advanced HNSCC were treated at our institution with CRT (n?=?194; 73?%) with three cycles of cisplatin (100 mg/m², every 3 weeks) or BRT (n?=?71; 27?%) with weekly cetuximab. Patients receiving BRT had more pre-existing conditions (Charlson index ≥?2) than the CRT group (p?=?0.005).

Results

Median follow-up was 29 months. In all, 56?% of patients treated with CRT received the planned three cycles (92?% at least two cycles) and 79?% patients treated with BRT received six cycles or more. The 2-year actuarial overall survival (OS) and progression-free survival (PFS) were 72?% and 61?%, respectively. In the multivariate analysis (MVA), T4 stage, N2–3 stage, smoking status (current smoker as compared with never smoker), and non-oropharyngeal locations predicted for OS, whereas BRT association with OS was of borderline significance (p?=?0.054). The 2-year actuarial locoregional control (LRC) and distant control (DC) rates were 73 and 79?%, respectively. CRT was independently associated with an improved LRC (2-year LRC: 76?% for CRT vs. 61?% for BRT) and DC (2-year LRC: 81?% for CRT vs. 68?% for BRT) in comparison with BRT (p?p?=?0.01 in the MVA). Subgroup analyses showed that T4 patients benefited significantly from CRT (vs. BRT) in LRC, while T1–3 did not. BRT patients had more G3–4 skin complications (p?p?=?0.006) and G3–4 gastrointestinal toxicities (p?Conclusion This retrospective analysis showed a better LRC in locally advanced HNSCC treated by cisplatin-based CRT than cetuximab-based BRT, and a nonsignificant trend towards an improved OS.     

Hyperfractionated accelerated radiation therapy plus cetuximab plus cisplatin chemotherapy in locally advanced inoperable squamous cell carcinoma of the head and neck

Background

Cetuximab (CET) is a potent inhibitor of the epidermal growth factor receptor and has been shown to have activity in squamous cell carcinoma of the head and neck (SCCHN). We conducted a single-arm phase II trial of a combination therapy comprising cisplatin (CIS), CET and hyperfractionated accelerated radiotherapy (HART).

Patients and methods

Patients with UICC stage III or IVA/B, M0 SCCHN were enrolled and treated with an initial dose of CET (400?mg/m²) and then with a weekly dosage of 250?mg/m² during HART. HART was started with a prescribed dosage of 2.0?Gy per day for 3 weeks, followed by 1.4?Gy twice daily to a total dose of 70.6?Gy to the gross tumour volume. CIS (40?mg/m²) was administered weekly (days 1, 8, 15, 22, 29 and 36). The primary objective of the phase II study was to determine the 2?year progression-free survival (PFS).

Results

Between November 2007 and November 2010, a total of 74?patients were enrolled in the study, of whom 65 were evaluable (83% were men). Median age was 56 years (range 37–69 years). An Oropharyngeal primary tumour was diagnosed in 49%, T4a,b in 65% and N2/3 in 96% of the patients. Of these patients, 85% were smokers or ex-smokers. Complete remission (CR) was observed in 23 patients (35%). The most common toxicity grade was ≥3, including mucositis (58%) and dysphagia (52%). The 2? and 5?year overall survival rates were 64 and 41%, the 2? and 5?year PFS rates were 45 and 32%, and the 2? and 5?year locoregional control rates were 47 and 33%, respectively.

Conclusion

The combination of weekly CIS with HART plus CET is a feasible regimen for these unfavourable smoking-induced cancers. However, the parallel US study (RTOG 0522) showed no advantage of the enhanced triple therapy compared to chemoradiotherapy alone.

     

Feasibility of 6-month maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck

Background

Close resection margins <?5 mm (CM) or extra capsular extent at the lymph nodes (ECE) impair the prognosis of patients with squamous cell cancer of the head and neck (SCCHN) scheduled for adjuvant radiochemotherapy. We conducted a multicenter phase II study to investigate toxicity and efficacy of additional cetuximab administered concomitantly and as maintenance for the duration of 6 months following adjuvant radiochemotherapy., Ppreliminary results on feasibility and acute toxicity on skin and mucosa are presented in this article.

Methods

Patients with SCCHN following CM resection or with ECE were eligible for the study. In all, 61.6 Gy (1.8/2.0/2.2 Gy, days 1–36) were administered using an integrated boost intensity-modulated radiotherapy (IMRT) technique. Cisplatin (20 mg/m², days 1–5 and days 29–33) and 5-fluorouracil (5-FU) as continuous infusion (600 mg/m², days 1–5 + days 29–33) were given concurrently. Cetuximab was started 7 days prior to radiochemotherapy at 400 mg/m² followed by weekly doses of 250 mg/m². Maintenance cetuximab began after radiochemotherapy at 500 mg/m² every 2 weeks for 6 months.

Results

Of the 55 patients (46 male, 9 female, mean age 55.6, range 29–70 years) who finished radiochemotherapy, 50 were evaluable for acute toxicity concerning grade III/IV toxicities of skin and mucosa. Grade 3–4 (CTC 3.0) mucositis, radiation dermatitis, and skin reactions outside the radiation portals were documented for 46, 28, and 14?% of patients, respectively. One toxic death occurred (peritonitis at day 57). Cetuximab was terminated in 5 patients due to allergic reactions after the first application. In addition, 22?% of patients discontinued cetuximab within the last 2 weeks or at the end of radiochemotherapy. Of patients embarking on maintenance treatment, 80?% were still on cetuximab at 3 months and 63?% at 5 months. Concurrent and maintenance treatment with cetuximab could be administered as scheduled in 48?% of patients.

Conclusion

Adjuvant radiochemotherapy with concomitant and maintenance cetuximab is feasible and acute toxicities are within the expected range. Compliance within the first 3–5 months is moderate.     

Evaluation of recurrent squamous cell carcinoma of the head and neck with FDG positron emission tomography

PURPOSE: This study compared the effectiveness of fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT), magnetic resonance imaging (MRI), or both for the assessment of recurrent squamous cell carcinoma of the head and neck. The value of quantifying the standardized uptake values (SUV) to distinguish recurrent neoplasm from inflammatory lesions and normal structures was also evaluated. METHODS: Forty-three patients with head and neck cancer were examined with F-18 FDG PET at least 4 months after their last course of radiation therapy (mean, 11 months). The SUVs were measured in visually identified regions of abnormally increased activity and were compared with the values in normal mucosa, the base of the tongue, and the hard palate to determine if an optimal cutoff value exists for diagnosing recurrence of malignant lesions. The final diagnosis of recurrence was made based on biopsy or at least 6 months' clinical follow-up. RESULTS: FDG PET correctly detected recurrence in 20 of 22 patients who had 45 discrete lesions located in the field of the upper aerodigestive tract. Two false-negative and three false-positive results were identified. The accuracy of FDG PET was 88% (38 of 43 patients), compared with 66% (25 of 38 patients) for CT, MRI, or both. Although there was a significant difference of SUVs (P = 0.0036) between the recurrent lesions and normal structures, the optimal cutoff values were difficult to define. CONCLUSIONS: Visual analysis of FDG PET is significantly more accurate in the diagnosis of recurrent squamous cell cancer of the head and neck than are CT or MRI. However, single SUV quantification does not significantly enhance efficacy.     

Prospective phase II trial of cetuximab plus VMAT-SIB in locally advanced head and neck squamous cell carcinoma

Introduction

Cetuximab plus radiotherapy (RT) may be an effective alternative to chemoradiation in locally advanced head and neck squamous cell carcinoma (LASCCHN) patients. We analyzed a group of patients treated at our institute with cetuximab plus volumetric modulation arc therapy (VMAT) with the RapidArc technique in a simultaneous integrated boost (SIB) regime. The primary end point was the assessment of acute toxicity and the feasibility of the combined approach.

Materials and methods

Between December 2008 and March 2010, 22?patients were submitted to IMRT-SIB plus cetuximab for radical intent in case of LASCCHN. None of the patients was suitable for chemotherapy because of important comorbidities (the majority suffered of heart chronic diseases). All patients underwent planning CT (additional image modalities were acquired for contouring purposes in the same treatment position: MRI in 12 and FDG-PET in 4?out of 22?patients). VMAT, by means of RapidArc, and SIB with two dose levels of 54.45?Gy and 69.96?Gy in 33?fractions were adopted. All patients included in the analysis were concomitantly treated with cetuximab: administration of the drug was initiated 1?week before RT at a loading dose of 400?mg/m² body surface area over a period of 120?min, follow by a weekly 60?min infusion of 250 mg/m² for the duration of RT. Patients were assessed for toxicities according to the Radiation Therapy Oncology Group (RTOG) criteria.

Results

All but 2?patients completed treatment and achieved the minimum follow-up of 12?months after the end of the treatment. Of the 22?patients, 18% (4?patients) showed grade?1, 36% (8?patients) grade?2, and 36% (8?patients) showed grade?3 dermatitis, while 9% (2?patients) had grade?1, 36% (8?patients) grade?2, and 45% (10?patients) had grade?3 mucositis/stomatitis. No grade?4 toxicities were recorded. Considering blood parameters, 3?cases of grade?1 anemia and 1?case of grade?2 thrombocytopenia were observed. Nobody required feeding tube placement during treatment.

Conclusion

The here reported toxicity data are promising and encouraging in regard to the adoption of moderate hypofractionation with VMAT-SIB techniques, when cetuximab is concomitantly administered.     

Acute toxicity in 14 patients with locally advanced head and neck squamous cell carcinoma treated with concurrent cetuximab and radiotherapy

Purpose

The authors report acute toxicity in 14 patients with locally advanced head and neck squamous cell carcinoma treated with radiotherapy and cetuximab.

Materials and methods

Data collection was performed prospectively on patients treated from September 2007 to March 2009. Treatment consisted of 64.8?C70 Gy radiotherapy in conventional fractions and cetuximab.

Results

Two out of 14 patients did not complete the planned combined treatment; radiotherapy was temporarily suspended in six other patients. Seven of 12 patients received cetuximab until the end of radiotherapy. Treatment breaks were principally due to severe acute cutaneous or mucous toxicity. Any grade acneiform rash occurred in all patients. In-field G3-4 cutaneous toxicity occurred in five (36%) patients and G3-4 mucous toxicity in seven (50%). One patient died of sepsis.

Conclusions

In our experience, severe acute toxic reactions are common in patients treated with radiotherapy and concurrent cetuximab, resulting in frequent breaks or incomplete treatment with potential reduction in disease control.     

Combination chemotherapy of advanced squamous carcinoma of the head and neck.

Combination chemotherapy in advanced squamous carcinoma of the head and neck resulted in objective remission in 5 of 8 patients, with a median duration of 9 months. In 4 patients, the intravenous chemotherapy was supplemented by regional intra-arterial short-time infusion chemotherapy, by which one patient obtained a partial remission and 3 a static disease. The most important results of the methods used were the subjective improvements of the patients. The side-effects were acceptable, and no serious complications were observed.     

The effect of cilengitide in combination with irradiation and chemotherapy in head and neck squamous cell carcinoma cell lines

Background

Integrins are highly attractive targets in oncology due to their involvement in angiogenesis in a wide spectrum of cancer entities. Among several integrin inhibitors under clinical evaluation, cilengitide is the most promising compound. However, little is known about the cellular processes induced during cilengitide therapy in combination with irradiation and cisplatin in head and neck squamous cell carcinoma (HNSCC).

Materials and methods

The cytostatic effect of cilengitide was assessed by proliferation assay in the three HNSCC cell lines SCC25, FaDu and CAL27. Combination experiments with cisplatin and irradiation were performed. Possible synergistic effects were calculated in combination index (CI) analyses. Colony forming inhibition was investigated in clonogenic assays. Real-time PCR arrays were used to evaluate target protein gene expression patterns. Flow cytometry was used to detect apoptosis.

Results

Used alone, cilengitide has only minor cytotoxic effects in HNSCC cell lines. However, combination with cisplatin resulted in synergistic growth inhibition in all three cell lines. Irradiation showed synergism in short-term experiments and in colony forming assays, an additive effect was detected. Real-time PCR assay detected downregulation of the antiapoptotic protein Bcl-2 after exposure of cells to cilengitide.

Conclusion

Cilengitide in combination with cisplatin and irradiation may be a feasible option for the treatment of patients with head and neck cancer. However, further investigations are required to understand the exact mechanism that leads to synergistic cytotoxicity.