Summary Background Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck ...(SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. Methods This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m2 on day 1 of each cycle) and fluorouracil (1000 mg/m2 on days 1–4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov , number NCT00460265. Findings Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8–12·2) in the panitumumab group and 9·0 months (8·1–11·2) in the control group (hazard ratio HR 0·873, 95% CI 0·729–1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6–6·6) in the panitumumab group and 4·6 months (4·1–5·4) in the control group (HR 0·780, 95% CI 0·659–0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 19% of 325 included in safety analyses vs six 2% of 325), diarrhoea (15 5% vs four 1%), hypomagnesaemia (40 12% vs 12 4%), hypokalaemia (33 10% vs 23 7%), and dehydration (16 5% vs seven 2%). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months 95% CI 9·7–13·7 vs 8·6 months 6·9–11·1; HR 0·73 95% CI 0·58–0·93; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months 7·3–12·9 vs 12·6 months 7·7–17·4; 1·00 0·62–1·61; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 95% CI 0·47–1·04). Interpretation Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings. Funding Amgen Inc.
Summary Background We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced ...squamous-cell carcinoma of the head and neck. Methods In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m2 during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70–72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov , number NCT00547157. Findings Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47–72) in the chemoradiotherapy group and 51% (40–62) in the radiotherapy plus panitumumab group. The most frequent grade 3–4 adverse events were mucosal inflammation (25 40% of 62 patients in the chemoradiotherapy group vs 37 42% of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 32% vs 36 40%), and radiation skin injury (seven 11% vs 21 24%). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. Interpretation Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III–IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. Funding Amgen.
Summary Background Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, ...locally advanced squamous-cell carcinoma of the head and neck. Methods In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m2 ) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9·0 mg/kg every 3 weeks plus cisplatin 75 mg/m2 ) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov , number NCT00500760. Findings Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54–78) in the chemoradiotherapy group and 61% (50–71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3–4 adverse events were dysphagia (17 27% of 63 patients in the chemoradiotherapy group vs 35 40% of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 24% vs 48 55%), and radiation skin injury (eight 13% vs 27 31%). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. Interpretation In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. Funding Amgen.
Background
Conformal radiotherapy is a primary treatment in head and neck cancer, which putative adverse effects depend on relatively low doses of radiation delivered to increased volumes of normal ...tissues. Systemic effects of such treatment include radiation-induced changes in serum lipid profile, yet dose- and volume-dependence of these changes remain to be established.
Methods
Here we analyzed levels of choline-containing phospholipids in serum samples collected consecutively during the radiotherapy used as the only treatment modality. The liquid chromatography–mass spectrometry (LC-MS) approach applied in the study enabled the detection and quantitation of 151 phospholipids, including (lyso)phosphatidylcholines and sphingomyelins.
Results
No statistically significant differences were found in the pretreatment samples from patients with different locations and stages of cancer. To compensate for potential differences between schemes of radiotherapy, the biologically effective doses were calculated and used in the search of correlations with specific lipid levels. We found that the levels of several phospholipids depended on the maximum dose delivered to the gross tumor volume and total radiation energy absorbed by the patient’s body. Increased doses correlated with increased levels of sphingomyelins and reduced levels of phosphatidylcholines. Furthermore, we observed several phospholipids whose serum levels correlated with the degree of acute radiation toxicity.
Conclusion
Noteworthy, serum phospholipid levels were associated mainly with volumes of normal tissues irradiated with relatively low doses (i.e., total accumulated dose 20 Gy), which indicated the importance of such effects on the systemic response of the patient’s organism to intensity-modulated radiotherapy (IMRT).
Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this ...meta-analysis was to assess whether this type of radiotherapy could improve survival.
Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction.
15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III–IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3·4% at 5 years (hazard ratio 0·92, 95% CI 0·86–0·97; p=0·003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1·7% with total dose reduction at 5 years, p=0·02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6·4% at 5 years; p<0·0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0·78 0·65–0·94 for under 50 year olds, 0·95 0·83–1·09 for 51–60 year olds, 0·92 0·81–1·06 for 61–70 year olds, and 1·08 0·89–1·30 for over 70 year olds; test for trends p=0·007).
Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.
Oral mucositis (OM) is a debilitating toxicity of chemoradiotherapy for head and neck cancer (HNC). This randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of ...palifermin to reduce OM associated with definitive chemoradiotherapy for locally advanced HNC.
Patients receiving conventionally fractionated radiotherapy (2.0 Gy/d, 5 days/wk to 70 Gy) with cisplatin (100 mg/m(2) on days 1, 22, and 43) received palifermin (180 μg/kg) or placebo before starting chemoradiotherapy and then once weekly for 7 weeks. The primary end point was the incidence of severe, observable, and functional OM (WHO grade 3 to 4).
The palifermin (n = 94) and placebo (n = 94) arms were well balanced. The incidence of severe OM was significantly lower for palifermin than for placebo (54% v 69%; P = .041). In the palifermin arm, median time to severe OM was delayed (47 v 35 days), median duration of severe OM was shortened (5 v 26 days), and the incidence of xerostomia grade ≥ 2 was lower (67% v 80%), favoring palifermin; however, the differences were not significant after multiplicity adjustment. Opioid analgesic use, average mouth and throat soreness scores, and chemoradiotherapy compliance were not significantly different between treatment arms. Adverse events were similar between arms (98%, palifermin; 93%, placebo). The most common study drug-related adverse events were rash, flushing, and dysgeusia. After median follow-up of 25.8 months, overall survival and progression-free survival were similar between treatment arms.
Although palifermin reduced severe functional OM, its role in the management of locally advanced HNC during chemoradiotherapy remains to be elucidated.
Anticancer treatment induces systemic molecular changes that could be detected at the level of biofluids. Understanding how human metabolism is influenced by these treatments is crucial to predict ...the individual response and adjust personalized therapies. Here, we aimed to compare profiles of metabolites in serum of head and neck cancer patients treated with concurrent chemo-radiotherapy, radiotherapy alone, or induction chemotherapy. Serum samples were analyzed by a targeted quantitative approach using combined direct flow injection and liquid chromatography coupled to tandem mass spectrometry, which allowed simultaneous quantification of 149 metabolites. There were 45 metabolites whose levels were significantly changed between pretreatment and within- or post-treatment serum samples, including 38 phospholipids. Concurrent chemo-radiotherapy induced faster and stronger effects than radiotherapy alone. On the other hand, chemotherapy alone did not result in significant changes. The decreased level of total phospholipids was the most apparent effect observed during the first step of the treatment. This corresponded to the loss of patients' body mass, yet no correlation between both parameters was observed for individual patients. We concluded that different molecular changes were measured at the level of serum metabolome in response to different treatment modalities.
Cancer radiotherapy (RT) induces response of the whole patient's body that could be detected at the blood level. We aimed to identify changes induced in serum lipidome during RT and characterize ...their association with doses and volumes of irradiated tissue. Sixty-six patients treated with conformal RT because of head and neck cancer were enrolled in the study. Blood samples were collected before, during and about one month after the end of RT. Lipid extracts were analyzed using MALDI-oa-ToF mass spectrometry in positive ionization mode. The major changes were observed when pre-treatment and within-treatment samples were compared. Levels of several identified phosphatidylcholines, including (PC34), (PC36) and (PC38) variants, and lysophosphatidylcholines, including (LPC16) and (LPC18) variants, were first significantly decreased and then increased in post-treatment samples. Intensities of changes were correlated with doses of radiation received by patients. Of note, such correlations were more frequent when low-to-medium doses of radiation delivered during conformal RT to large volumes of normal tissues were analyzed. Additionally, some radiation-induced changes in serum lipidome were associated with toxicity of the treatment. Obtained results indicated the involvement of choline-related signaling and potential biological importance of exposure to clinically low/medium doses of radiation in patient's body response to radiation.
•Nutritional counseling prevents weight loss in patients with head and neck cancer.•Nutritional counseling may contribute to increased overall survival in patients with head and neck cancer.•Weight ...loss is most pronounced in head and neck cancer patients with oral cavity or oropharyngeal cancer.•Weight loss is most pronounced in patients with head and neck cancer treated with chemotherapy.
Nutritional intervention, including nutritional counseling (NC), plays a significant role in the comprehensive management of patients with head and neck cancer (HNC). The aim of this study was to investigate the effects of NC combined with oral nutritional supplements during radical treatment on weight loss and survival outcomes in patients with HNC.
The study included 310 patients who received radical treatment for HNC. Among these patients, 119 underwent NC along with oral nutritional supplements (NCONS); 191 were supported with oral nutritional supplements only (ONS). The study aimed to investigate the effects of sex, disease stage, treatment modality, and tumor site on weight loss. Additionally, the Kaplan–Meier method assessed the influence of NC on overall survival and disease-free survival.
The present study suggested that the NC independently prevented weight loss, regardless of sex and disease stage (female: –1.6%, P = 0.001; male: –2.3 %, P = 0.003; T stage (0–2): –1.7%, P = 0.008; T stage (3–4): –2.7%, P = 0.003; N stage (0–1): 2.5%, P = 0,027; N stage (3–4): 2.9%, P < 0.001). The protective effect was most significant in patients with oral cancer and oropharyngeal cancer and in patients treated with chemotherapy (oral: –1.7%, P = 0.03; oropharynx: –3.3%, P < 0.001; radiochemotherapy: –3%, P = 0.028; induction chemotherapy preceded radiochemotherapy: –6%, P < 0.001). Furthermore, the 3-year overall survival rates were 93.4% and 85.4% in the NC along with oral nutritional supplements (NCONS) and oral nutritional supplement (ONS) groups, respectively (P = 0.031).
Patients with HNC who received NC during radical treatment experienced reduced weight loss. This effect was particularly pronounced in patients with oral cavity or oropharyngeal cancer and those undergoing chemotherapy. Additionally, NC was associated with improved overall survival in this patient cohort. Nevertheless, further studies are required to validate and support these findings.
The paper aims to show the multilevel and complex cooperation and the inclusion of the psychotherapist leading the psychotherapy in the medical team at the radiotherapy and clinical oncology clinic. ...We illustrate these interventions with the case of Stan. This 43‐year‐old firefighter was diagnosed with advanced head and neck cancer and pre‐existing mental health problems meeting the criteria of ICD‐10: obsessive‐compulsive disorder, post‐traumatic stress disorder and psychoactive substance abuse. During the treatment, suicidal thoughts and impulses emerged, triggered at the hospital by electronic noises and the feeling of entrapment without a way out. This situation put the patient at high risk and the whole healthcare team needed an urgent effective response. The patient agreed to stay in the secured room, where he was cared for by doctors, nurses, a dietitian, and a psychotherapist. He actively attended daily sessions with noticeable engagement. Psychotherapy sessions focused on alleviating posttraumatic stress disorder and OCD. Mindfulness and breathwork‐based exercises were implemented to increase non‐judgemental self‐awareness and regulate the over‐aroused nervous system. As a result, the patient's mental health has improved and the completion of the cancer treatment was possible. Psychotherapy, good therapeutic alliance, and attentive teamwork effectively managed his mental health and treatment‐related symptoms.
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