Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients

There has been concern that long-term supplementation with high-dose antioxidant vitamins, especially vitamin E (alpha-tocopherol), may increase all-cause mortality. We conducted a randomized controlled trial with alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day) supplements among 540 head and neck cancer patients treated by radiation therapy. Supplementation with beta-carotene was discontinued during the trial. The supplements were given during radiation therapy and for 3 additional years. During the follow-up (median 6.5 years), 179 deaths were recorded. All death certificates were obtained. All-cause and cause-specific mortality rates were compared between the 2 arms of the trial by Cox regression. All-cause mortality was significantly increased in the supplement arm: hazard ratio: 1.38, 95% confidence interval 1.03-1.85. Cause-specific mortality rates tended to be higher in the supplement arm than in the placebo arm. Our results concur with previous reports to suggest that high-dose vitamin E could be harmful.     

Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial

Randomized trials have shown, unexpectedly, that supplementation with selenium or vitamin E is associated with a reduction of prostate cancer risk. We assess whether a supplementation with low doses of antioxidant vitamins and minerals could reduce the occurrence of prostate cancer and influence biochemical markers. The SU.VI.MAX trial comprised 5,141 men randomized to take either a placebo or a supplementation with nutritional doses of vitamin C, vitamin E, beta-carotene, selenium and zinc daily for 8 years. Biochemical markers of prostate cancer risk such as prostate-specific antigen (PSA) and insulin-like growth factors (IGFs) were measured on plasma samples collected at enrollment and at the end of follow-up from 3,616 men. Cox regression models were used to estimate the hazard ratio and related 95% confidence interval of prostate cancer associated with the supplementation and to examine whether the effect differed among predetermined susceptible subgroups. During the follow-up, 103 cases of prostate cancer were diagnosed. Overall, there was a moderate nonsignificant reduction in prostate cancer rate associated with the supplementation (hazard ratio = 0.88; 95% CI = 0.60-1.29). However, the effect differed significantly between men with normal baseline PSA (< 3 microg/L) and those with elevated PSA (p = 0.009). Among men with normal PSA, there was a marked statistically significant reduction in the rate of prostate cancer for men receiving the supplements (hazard ratio = 0.52; 95% CI = 0.29-0.92). In men with elevated PSA at baseline, the supplementation was associated with an increased incidence of prostate cancer of borderline statistical significance (hazard ratio = 1.54; 95% CI = 0.87-2.72). The supplementation had no effect on PSA or IGF levels. Our findings support the hypothesis that chemoprevention of prostate cancer can be achieved with nutritional doses of antioxidant vitamins and minerals.     

Trends in head and neck cancer incidence in relation to smoking prevalence

The trends in head and neck cancer incidence and smoking prevalence are reviewed, discussing where such trends parallel but also how and why they may not. In the U.S., public health efforts at tobacco control and education have successfully reduced the prevalence of cigarette smoking, resulting in a lower incidence of head and neck cancer. Vigilance at preventing tobacco use and encouraging cessation should continue, and expanded efforts should target particular ethnic and socioeconomic groups. However, an unfortunate stagnation has been observed in oropharyngeal cancer incidence and likely reflects a rising attribution of this disease to oncogenic human papillomavirus, in particular type 16 (HPV-16). For the foreseeable future, this trend in oropharyngeal cancer incidence may continue, but with time the effects of vaccination of the adolescent and young adult female population should result in a lower viral prevalence and hopefully a reduced incidence of oropharyngeal cancer. To hasten the reduction of HPV-16 prevalence in the population, widespread vaccination of adolescent and young adult males should also be considered.     

Global and health-related quality of life after intensity-modulated radiation therapy for head and neck cancer

This study aims to evaluate the current literature regarding the effects of conventional radiation therapy (CRT) versus intensity-modulated radiation therapy (IMRT) on global quality of life (QoL) among patients treated for head and neck cancer. A PubMed literature review was performed. Only articles comparing global QoL scores in head and neck cancer patients treated with CRT versus IMRT were included. Studies were scrutinized for methodology, level of evidence and limitations. Outcomes were evaluated for external validity, level of evidence and applicability. Between 2005 and 2012, 14 eligible studies (six prospective, two randomized controlled trials) were identified. Although all presented data comment on the advantages of IMRT, differences in study design made comparisons difficult. The vast majority of these were also limited by relatively small sample sizes and heterogeneity with respect to patient and treatment-related characteristics. Although more robust evidence is needed in the future, the published data reasonably support the benefits of IMRT as compared with CRT (either 2D or 3D) in improving QoL, beginning at approximately 3–6 months post-treatment, and possibly potentiating with time up to 2 and 3 years.     

利用0.13cc电离室对头颈部肿瘤调强放疗计划的剂量学验证

目的:利用0.13cc电离室对头颈部肿瘤调强适形放射治疗(IMRT)计划进行剂量学验证.方法:将20例头颈部肿瘤患者的IMRT计划分别移植到经过CT扫描的调强体模,生成验证计划,将0.13cc电离室放置到调强体模中在加速器下执行验证计划,在治疗计划系统中算出电离室所在区域的吸收剂量为计划剂量,按验证计划照射测量到的电离室吸收剂量为实测剂量,将二者进行比较得出误差.相对误差=(计划剂量-实测剂量)/实测剂量.百分误差超过±5％,说明计划在执行中剂量误差过大,计划需要修正.结果:20例患者中有17例患者验证的误差在±5％以内,表明计划通过;有3例患者误差超过±5％以内,计划需重新修改,计划通过率为85％.结论:剂量学验证确定IMRT治疗剂量的置信度,保证治疗计划的准确实施,提供了临床评价治疗计划的依据.     

Tobacco smoking and alcohol drinking at diagnosis of head and neck cancer and all‐cause mortality: Results from head and neck 5000, a prospective observational cohort of people with head and neck cancer

Tobacco smoking and alcohol consumption are well‐established risk factors for head and neck cancer. The prognostic role of smoking and alcohol intake at diagnosis have been less well studied. We analysed 1,393 people prospectively enrolled into the Head and Neck 5000 study (oral cavity cancer, n=403; oropharyngeal cancer, n=660; laryngeal cancer, n=330) and followed up for a median of 3.5 years. The primary outcome was all‐cause mortality. We used Cox proportional hazard models to derive minimally adjusted (age and gender) and fully adjusted (age, gender, ethnicity, stage, comorbidity, body mass index, HPV status, treatment, education, deprivation index, income, marital status, and either smoking or alcohol use) mortality hazard ratios (HR) for the effects of smoking status and alcohol intake at diagnosis. Models were stratified by cancer site, stage and HPV status. The fully‐adjusted HR for current versus never‐smokers was 1.7 overall (95% confidence interval [CI] 1.1, 2.6). In stratified analyses, associations of smoking with mortality were observed for oropharyngeal and laryngeal cancers (fully adjusted HRs for current smokers: 1.8 (95% CI=0.9, 3.40 and 2.3 (95% CI=0.8, 6.4)). We found no evidence that people who drank hazardous to harmful amounts of alcohol at diagnosis had a higher mortality risk compared to non‐drinkers (HR=1.2 (95% CI=0.9, 1.6)). There was no strong evidence that HPV status or tumour stage modified the association of smoking with survival. Smoking status at the time of a head and neck cancer diagnosis influenced all‐cause mortality in models adjusted for important prognostic factors.     

Randomized trial of conventional versus high fractional dose radiation therapy in the treatment of advanced head and neck cancer

A prospectively randomized clinical trial was undertaken to compare conventionally fractionated radiation therapy and high fractional dose irradiation in the treatment of advanced, surgically unresectable head and neck squamous cell carcinoma. Sixty-four patients were entered into the study between 1973 and 1979 and were randomized to receive either 200 rad daily to total tumor doses of 6000-7000 rad in 6-7 weeks, or 400 rad daily to a total of approximately 4400 rad in 2-3 weeks. The distribution of patients between the two fractionation schedules was comparable regarding site of the primary tumor, extent of disease, degree of histologic differentiation and performance status. Twenty-nine of 31 (94%) patients in the 200 rad group and 29 of 33 (88%) in the 400 rad group has Stage IV disease. Twenty-six in the former group and 30 in the latter completed radiation therapy as planned. Acute skin and mucosal reactions occurred earlier in patients treated with 400 rad daily, but were of equivalent intensity and well within acceptable levels in both groups. No increase in late adverse effects was seen with high daily doses. Palliation of tumor-related symptoms and extent of tumor control were comparable in the two groups. Actuarial five year disease-free survival rates were approximately 10% in both treatment groups with a mean follow-up period of 5 1/2 years. We conclude that high fractional dose irradiation is equivalent to conventionally fractionated radiation therapy in the treatment of advanced head and neck cancer.     

Neutron therapy for head and neck cancer: II. Further follow-up on the M. D. Anderson TAMVEC randomized clinical trial

Between January 1977 and February 1980, 95 patients with inoperable squamous carcinomas of the head and neck were treated in a two-armed randomized clinical trial comparing 1) mixed schedule irradiation using two neutron and three photon fractions per week and 2) standard photon irradiation. Complete tumor regression was achieved in 80% of patients treated with mixed-schedule irradiation, and in 68% of patients treated with photons. The local control rate was 44% in patients treated with mixed-schedule irradiation and 41% in patients treated with photons. There were four complications of treatment in each treatment arm. Absolute survival was 20% with mixed-schedule treatment and 17% in photons. Actuarial analysis shows superior local control and survival rates with mixed-schedule irradiation over photons only in the first two years.     

Result of two randomized trials comparing nolatrexed (ThymitaqTM) versus methotrexate in patients with recurrent head and neck cancer

We report on two randomized trials performed in the USA and Europe,which compared methotrexate and nolatrexed as treatment for patientswith recurrent head and neck cancer. Eligibility criteria included:histologically confirmed squamous-cell carcinoma, measurable disease,adequate hematological, renal and hepatic functions, failure of afirst-line chemotherapy, and informed consent. Methotrexate 40mg/m² was weekly given by short infusion, and nolatrexed 725mg/m² per day was administered as a five-day continuousinfusion, every three weeks. A total of 139 patients (63 in the USA, 76in Europe) were randomized based on a ratio of 2/1: 93 and 46 receivednolatrexed and methotrexate, respectively. Patient characteristicsincluded 115 males and 24 females; median age 60 years. In thenolatrexed arm, the following grade 3–4 toxicities occurred:neutropenia (29.9%) with 3.1% of febrile neutropenia,mucositis (33.3%), and vomiting (10.3%). In the MTX arm,the grade 3–4 toxicities were neutropenia (7.1%) andmucositis (6.9%). There was no difference in activity between thenolatrexed and the methotrexate treatment: 3.3% and 10.8%of objective responses, 1.9 versus1.5 months ofdisease-free progression and 3.5 versus3.7 months of overallsurvival, respectively. Nolatrexed has demonstrated a similar activityto methotrexate.     

The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy

PURPOSE: A common side effect experienced by head and neck cancer patients after radiation therapy (RT) is impairment of the parotid glands' ability to produce saliva. Our purpose is to investigate the relationship between radiation dose and saliva changes in the 2 years after treatment. METHODS AND MATERIALS: The study population includes 142 patients treated with conformal or intensity-modulated radiotherapy. Saliva flow rates from 266 parotid glands are measured before and 1, 3, 6, 12, 18, and 24 months after treatment. Measurements are collected separately from each gland under both stimulated and unstimulated conditions. Bayesian nonlinear hierarchical models were developed and fit to the data. RESULTS: Parotids receiving higher radiation produce less saliva. The largest reduction is at 1-3 months after RT followed by gradual recovery. When mean doses are lower (e.g., <25 Gy), the model-predicted average stimulated saliva recovers to pretreatment levels at 12 months and exceeds it at 18 and 24 months. For higher doses (e.g., >30 Gy), the stimulated saliva does not return to original levels after 2 years. Without stimulation, at 24 months, the predicted saliva is 86% of pretreatment levels for 25 Gy and <31% for >40 Gy. We do not find evidence to support that the overproduction of stimulated saliva at 18 and 24 months after low dose in 1 parotid gland is the result of low saliva production from the other parotid gland. CONCLUSIONS: Saliva production is affected significantly by radiation, but with doses <25-30 Gy, recovery is substantial and returns to pretreatment levels 2 years after RT.     

Phase 2 trial of concurrent 5‐fluorouracil,hydroxyurea, cetuximab,and hyperfractionated intensity‐modulated radiation therapy for locally advanced head and neck cancer

BACKGROUND:

The objective of this phase 2 study was to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated‐boost (SIB), intensity‐modulated radiation therapy (IMRT) into a well described 5‐fluorouracil (5‐FU) and hydroxyurea (HU)‐based chemoradiation regimen.

METHOD:

Patients with stage IVA and IVB or high‐risk stage III squamous cell carcinomas of the head and neck were enrolled on a phase 2 trial. Prior organ‐conserving surgery or induction chemotherapy was allowed off protocol. SIB‐IMRT was prescribed to low‐risk volumes (43.2 gray [Gy] to 48 Gy) and intermediate‐risk volumes (54‐63 Gy). A separate IMRT cone‐down plan was targeted to macroscopic disease (72 Gy). The median radiation dose was 72 Gy (range, 60‐72 Gy) administered in 1.5 Gy fractions twice daily during Weeks 1, 3, 5, 7 and 9. Concurrent systemic therapy consisted of 5‐FU (600 mg/m²), HU (500 mg twice daily), and cetuximab (250 mg/m²).

RESULTS:

From January 2007 through April 2008, 33 patients were enrolled. At a median follow‐up of 24 months, the 2‐year rates of locoregional control, distant control, disease‐free survival, and overall survival were 83%, 79%, 69%, and 86%, respectively. Grade 3 toxicity consisted of mucositis in 33% of patients, radiation dermatitis in 15%of patients, anemia in 18% of patients, leukopenia in 18% of patients, neutropenia in 12% of patients, and thrombocytopenia in 3% of patients. Most patients (64%) were able to tolerate treatment without a feeding tube, and there were no acute or late grade ≥4 adverse events.

CONCLUSIONS:

The current results indicated that concurrent 5‐FU, HU, and cetuximab plus SIB‐IMRT is a promising and reasonably well tolerated approach to incorporating molecularly targeted therapy into curative therapy for patients with locally advanced head and neck cancer. Cancer 2011. © 2010 American Cancer Society.