A historical prospective cohort study of carotid artery stenosis after radiotherapy for head and neck malignancies

PURPOSE: To determine carotid artery stenosis incidence after radiotherapy for head-and-neck neoplasms. METHODS AND MATERIALS: This historical prospective cohort study comprised 44 head-and-neck cancer survivors who received unilateral neck radiotherapy between 1974 and 1999. They underwent bilateral carotid duplex ultrasonography to detect carotid artery stenosis. RESULTS: The incidence of significant carotid stenosis (8 of 44 [18%]) in the irradiated neck was higher than that in the contralateral unirradiated neck (3 of 44 [7%]), although this difference was not statistically significant (p = 0.13). The rate of significant carotid stenosis events increased as the time after radiotherapy increased. The risk of ipsilateral carotid artery stenosis was higher in patients who had undergone a neck dissection vs. those who had not. Patients with significant ipsilateral stenosis also tended to be older than those without significant stenosis. No other patient or treatment variables correlated with risk of carotid artery stenosis. CONCLUSIONS: For long-term survivors after neck dissection and irradiation, especially those who are symptomatic, ultrasonographic carotid artery screening should be considered.     

A prospective, comparative study on the early effects of local and remote radiation therapy on carotid intima-media thickness and vascular cellular adhesion molecule-1 in patients with head and neck and prostate tumors

Background and purpose

To investigate early vascular changes related to carotid atherosclerotic injury post-radiation therapy (RT), we studied carotid intima-media thickness (IMT) and vascular cellular adhesion molecule (VCAM)-1 at two time-points after RT and compared local and remote irradiation effects in patients with head and neck (HNC) and prostate cancer (PC), respectively.

Material and methods

We prospectively studied patients beginning RT for HNC or PC, performing carotid ultrasound before RT, early after and six months after treatment to measure carotid IMT. Blood samples were simultaneously collected to study VCAM-1 by ELISA.

Results

We studied 19 patients with HNC and 24 with PC. Patients with HNC were younger (55 ± 10 years) than PC patients (68 ± 8 years). Early post-RT only HNC patients had an increase in IMT compared to baseline measurements (0.73 ± 0.04 mm vs. 0.80 ± 0.05 mm, p = 0.029). On the other hand, VCAM-1 levels decreased in PC patients, remaining unchanged in HNC patients. Late post-RT (six months from previous assessment), neither IMT nor VCAM-1 values changed in both groups.

Conclusion

Local and remote RT seem to exert differential early effects regarding vascular-related changes: (1) local RT seems to affect vascular structure and increase IMT and (2) RT for PC is associated with reduction in VCAM levels, suggesting systemic modulation of cancer-related factors.     

Frequency,outcome and prognostic factors of carotid blowout syndrome after hypofractionated re-irradiation of head and neck cancer using CyberKnife: A multi-institutional study

Purpose

Re-irradiation has attracted attention as a potential therapy for recurrent head and neck tumors. However, carotid blowout syndrome (CBS) has become a serious complication of re-irradiation because of the associated life-threatening toxicity. Determining of the characteristics of CBS is important. We conducted a multi-institutional study.

Methods and patients

Head and neck carcinoma patients (n = 381) were treated with 484 re-irradiation sessions at 7 Japanese CyberKnife institutions between 2000 and 2010.

Results

Of these, 32 (8.4%) developed CBS, which proved fatal that median survival time after CBS onset was 0.1 month, and the 1-year survival rate was 37.5%. The median duration between re-irradiation and CBS onset was 5 months (range, 0–69 months). Elder age, skin invasion, and necrosis/infection were identified as statistically significant risk factors after CBS by univariate analysis. The presence of skin invasion at the time of treatment found only in postoperative case, is identified as only statistically significant prognostic factor after CBS in multivariate analysis. The 1-year survival rate for the group without skin invasion was 42%, whereas no patient with skin invasion survived more than 4 months (0% at 1 year, p = 0.0049).

Conclusions

Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion at CBS onset is ominous sign of lethal consequences.     

Fatigue during head-and-neck radiotherapy: prospective study on 117 consecutive patients

PURPOSE: Fatigue is an underevaluated cancer-related and treatment-related symptom. We analyzed fatigue in head and neck cancer patients undergoing radiotherapy (RT). METHODS AND MATERIALS: A total of 117 patients were enrolled (mean age, 58 years). Radiation therapy (median dose, 66 Gy) was given with either exclusive or postoperative intent in 52 and 65 patients, respectively. Chemotherapy (CT) was added before and/or during RT in 61 patients. The patients completed a 20-item questionnaire (Multidimensional Fatigue Inventory [MFI-20]) before, during (weekly), and after RT. The impact of patient-, tumor-, and treatment-related factors on fatigue was evaluated with unifactorial and multifactorial tests. RESULTS: Fatigue level increased during RT reaching a maximum at Week 6 and then slowly decreased. In multivariate stepwise regression analysis age (inversely related, p < 0.05), psychologic disorders (p < 0.005), and previous head-and-neck surgery (inversely related, p < 0.005) were correlated with higher pre-RT fatigue level. Pre-RT fatigue score (p < 0.0001), induction and/or concomitant CT (p = 0.035), need of cortisone during RT (p = 0.005), and thyroid disorders (p = 0.032) were correlated with higher during-RT fatigue level. Pre-RT fatigue score (p < 0.0001), induction and/or concomitant CT (p < 0.001), and need of cortisone during RT (p < 0.005) were correlated with higher post-RT fatigue level. No impact of gender, performance status, comorbidities other than psychologic and thyroid, tumor stage/site, RT intent, dose, volume, duration, or toxicity was observed. CONCLUSION: Fatigue affects all patients undergoing RT for head-and-neck cancer, reaches maximum score at the 6th week of RT, and slowly decreases thereafter. Age, thyroid dysfunction, psychologic disorders, pre-RT fatigue score, CT, and cortisone use are correlated with RT-related fatigue levels.     

The course of health-related quality of life in head and neck cancer patients treated with chemoradiation: A prospective cohort study

Background and purpose

To evaluate the course of health-related quality of life (HRQOL) from diagnosis to 2 years follow-up in patients with head and neck cancer (HNSCC) treated with chemoradiation (CRT).

Materials and methods

164 patients completed the EORTC QLQ-C30 and QLQ-H&N35 questionnaires 1 week before and 6 weeks and 6, 12, 18, and 24 months after CRT. Patients were compared to a reference group. A linear mixed-model analysis was used to assess changes in HRQOL over time, and whether this was associated with age, gender, comorbidity, and tumor sublocation.

Results

Significant differences for the majority of HRQOL scales were observed between patient and reference group at baseline, and follow-up. The course of HRQOL was different for survivors compared to non-survivors. In survivors, improvement over time was observed (in global quality of life, physical, role, and social function, fatigue, pain, swallowing, speech, social eating, and social contacts), while in non-survivors the pattern over time was either no changes in HRQOL or a deterioration (in physical function, social eating and contacts). In both survivors and non-survivors, emotional functioning improved after treatment, but deteriorated in the longer term. Patients with comorbidity reported worse physical function, and patients with oral/oropharyngeal cancer (compared to hypopharyngeal/laryngeal cancer) reported more oral pain and sexual problems, but fewer speech problems.

Conclusions

The course of HRQOL of HNSCC patients during the first 2 years after CRT is different for survivors compared to non-survivors and is associated with comorbidity and tumor subsite.     

Quality of life as predictor of survival: A prospective study on patients treated with combined surgery and radiotherapy for advanced oral and oropharyngeal cancer

Background and purpose

The relation between health-related quality of life (HRQOL) and survival was investigated at baseline and 6 months in 80 patients with advanced oral or oropharyngeal cancer after microvascular reconstructive surgery and (almost all) adjuvant radiotherapy.

Materials and methods

Multivariate Cox regression analyses of overall and disease-specific survival were performed including sociodemographic (age, gender, marital status, comorbidity), and clinical (tumor stage and site, radical surgical, metastasis, radiotherapy) parameters, and HRQOL (EORTC QLQ-C30 global quality of life scale).

Results

Before treatment, younger age and having a partner were predictors of disease-specific survival; younger age predicted overall survival. At 6 months post-treatment, disease-specific and overall survival was predicted by (deterioration of) global quality of life solely. Global health-related quality of life after treatment was mainly influenced by emotional functioning.

Conclusion

Deterioration of global quality of life after treatment is an independent predictor of survival in patients with advanced oral or oropharyngeal cancer.     

Evaluation of comorbidity in 9388 head and neck cancer patients: A national cohort study from the DAHANCA database

Background

Comorbidity is common in head and neck squamous cell carcinoma (HNSCC) patients due to the etiology of the disease being primarily smoking. The aim of this study was to investigate the impact of comorbidity on survival in a national population-based cohort study on 9388 HNSCC-patients treated with radiotherapy (RT), to re-evaluate the prognostic impact of individual diseases within the Charlson Comorbidity Index (CCI), and to develop a revised head and neck comorbidity index (HN-CCI).

Material and methods

A national cohort of 9388 HNSCC-patients treated with curative intended RT diagnosed from 1992 to 2008 was identified from the DAHANCA-database. Data on comorbidity prior to HNSCC-diagnosis was obtained from the National Patient Registry and adapted to the CCI.

Results

By dividing the patients into two groups, we tested and validated which type of comorbidities within the CCI affected overall survival (OS) and cancer specific death (CSD). In total, 36% of patients had comorbidity. Six comorbid conditions within the CCI significantly reduced five-year OS probability: congestive heart failure, cerebrovascular disease, chronic pulmonary disease, peptic ulcer disease, liver disease, and diabetes, and based on these conditions the new head and neck specific comorbidity index was developed, the HN-CCI. Comorbidity according to HN-CCI had a highly significant impact on OS, whereas it was not associated with CSD. Chronological age was not associated with increased risk of CSD after controlling for comorbidity.

Conclusions

Comorbidity is frequent in HNSCC patients and negatively impacts OS. Therefore assessment of comorbidity will be of great importance, both in order to treat/optimize patient’s health before radiotherapy, but also in order to be able to stratify/control for comorbidity in randomized trials to avoid bias. Re-evaluation of the CCI revealed that only six conditions had an impact on survival, and a new modified index to assess comorbidity for HNSCC-patients was developed. The performance of HN-CCI to stratify patients on survival was good and HN-CCI is highly recommended for future assessment of comorbidity and prognostic staging of radiotherapy-treated HNSCC-patients.     

Bleomycin, cyclophosphamide and radiotherapy in regionally advanced epidermoid carcinoma of the head and neck

We have treated 24 patients with squamous carcinoma of the head and neck and advanced regional (N2-3) disease. The regimen consisted of 3 cycles, each of 28 days. Cyclophosphamide (1 gm/m2 I.V.) was given on day 1, bleomycin (15 u I.M.) on days 2, 4, 9 and 11, and ionizing radiation (60Co, 180 rad/fraction) days 1-5, and 8-12. No therapy was given on days 13-28. After three cycles of therapy, 13 patients had a complete response; following further therapy (surgery, interstitial or external beam radiation), 16 patients were free of disease. However, remissions were not durable and 11/16 patients recurred loco-regionally with a median time to recurrence of 5 months; most (7/11 also developed distant metastases. These patients have biologically aggressive disease and may have a worse prognosis than patients who are Stage IV based on a T4 primary lesion only.     

Hypopharyngeal cancer: results of treatment with radiotherapy alone and combinations of surgery and radiotherapy

From 1962 to 1977, 90 patients with hypopharyngeal cancer were seen in the Academic Hospital in Leuven. Radiotherapy was the primary treatment in 66 patients, actuarial survival was 18% at 5 years and local control 22%. In 22 patients treated with a laryngopharyngectomy and pre- or postoperative radiotherapy, survival was also 18%, but local control was obtained in 51%. No differences in prognosis were demonstrated according to the tumoral stage or nodal status. Metastases were found in 10.5% of irradiated patients and in 14% of patients treated with combined therapy. The frequency of postoperative complications was not increased after surgery for preoperatively irradiated patients. Treatment results in hypopharyngeal cancer remain unfavorable, even with a combination of surgery and radiotherapy. Alternative approaches should be actively investigated to improve local control rates such as the modalities currently under study (high LET, new fractionations, combinations with drugs).     

Patterns of failure and toxicity after intensity-modulated radiotherapy for head and neck cancer

PURPOSE: To determine the outcome of patients treated with intensity-modulated radiotherapy (IMRT) for head and neck cancer. METHODS AND MATERIALS: We reviewed the charts of 100 consecutive patients treated with IMRT for squamous cell carcinoma of the oropharynx (64%), nasopharynx (16%), hypopharynx (14%), and larynx (6%). Most patients were treated with a concomitant boost schedule to 72 Gy. Of the 100 patients, 54 (54%) received adjuvant chemotherapy, mostly concurrent cisplatin. The dosimetry plans for patients with either locoregional failure or Grade 4-5 complications were reviewed and fused over the computed tomography images corresponding with the location of the event. Marginal failures were defined as those that occurred at a region of high-dose falloff, where conventional fields would have provided better coverage. RESULTS: The median follow-up of living patients was 3.1 years (range, 1-5.2 years). The 3-year rate of local control, locoregional control, freedom from relapse, cause-specific survival, and overall survival for all patients was 89%, 87%, 72%, 78%, and 71%, respectively. The 3-year rate of freedom from relapse, cause-specific survival, and overall survival for the 64 oropharynx patients was 86%, 92%, and 84%, respectively. Of the 10 local failures, 2 occurred at the margin of the high-dose planning target volume. Both regional failures occurred within the planning target volume. No locoregional failures occurred outside the planning target volume. Of the 100 patients, 8 and 5 had Grade 4 and 5 complications from treatment, respectively. All patients with Grade 5 complications had received adjuvant chemotherapy. No attempt was made to discriminate between the complications from IMRT and other aspects of the patients' treatment. CONCLUSION: Intensity-modulated radiotherapy did not compromise the outcome compared with what we have achieved with conventional techniques. The 2 cases of recurrence in the high-dose gradient region highlight the potential hazard of approaches that involve highly conformal dose distributions.     

Comparison of cervical esophagus dose-volumes for three radiotherapy techniques for head and neck cancer

PURPOSE: This study compares the radiation dose-volume of the cervical esophagus during head and neck radiotherapy using three different techniques. METHODS: Treatment plans of 58 patients from 3/04 to 1/06 treated with bilateral head and neck radiotherapy were analyzed retrospectively. A comparison of the cervical esophagus dose with three-field 3D conformal RT (3DRT, n=34), whole-field IMRT (WF-IMRT, n=12), and half-beam IMRT (HB-IMRT, n=12) was performed. The volumes of esophagus receiving > or =50Gy (V50), > or =54Gy (V54) and > or = 60Gy (V60) and lengths receiving circumferential dose > or = 50Gy (L50) and > or = 54Gy (L54) were evaluated. RESULTS: Maximum dose, V54 and L54 were greater for the first 2cm and entire cervical esophagus with WF-IMRT than HB-IMRT or 3DRT. In patients requiring a high match, WF-IMRT was associated with a greater maximum dose, V54 and L54 than HB-IMRT and 3DRT (p<0.05). In the low match group, WF-IMRT was associated with a greater V54 and L54 (p<0.05). Low neck disease, low primary site, and definitive radiotherapy were associated with increased irradiation of the esophagus. CONCLUSION: Treatment of the lower neck with IMRT is associated with increased irradiation to the cervical esophagus, and dose constraints should be included to reduce toxicity.     

The emerging role of cetuximab in head and neck cancer: a 2007 perspective

The integration of targeted therapies into clinical practice constitutes the paradigm of oncology treatment in the current era. Cetuximab, a recombinant human/mouse chimeric epidermal growth factor (EGFR) monoclonal antibody is a targeted agent that has seen expanding indication in recent years. Originally approved for colorectal cancer, its role in the treatment of squamous cell carcinoma of the head and neck has augmented treatment options for patients who are refractory to or cannot tolerate platinum. This article will review the science underlying cetuximab, data supportings its use in patients with locally advanced and recurrent/metastatic disease, common toxicities of therapy, and the integration of this treatment with radiation therapy.     

Molecular biomarkers and site of first recurrence after radiotherapy for head and neck cancer

The prognostic significance of a panel of molecular biomarkers in head and neck squamous cell carcinoma (HNSCC) for first failure site (primary (T), nodal (N) or distant (M)) was analysed in 309 patients randomised to continuous hyperfractionated accelerated radiotherapy (CHART) vs. conventionally fractionated radiotherapy. Multivariate competing risks analysis was performed using an accelerated failure-time model. First-order interactions between each marker and trial arm were also tested. Bcl2-positivity increased the time to T- and N-failures, increasing cyclin D1 score decreased the time to N-failures. A random proliferative pattern and low Ki-67 decreased the time to M-failures. A high CD31 score was associated with a significantly longer time to T-failure after CHART, but not after conventional fractionation. Risks of T-, N- and M-failures could be estimated for individual patients. Competing risks analysis of failure sites allows the rational selection of patients for more aggressive loco-regional or systemic therapy.     

Palliative radiotherapy for locally advanced non-metastatic head and neck cancer: A systematic review

Objectives: The objective of this systematic review was to identify and appraise the existing evidence of role of palliative radiotherapy for locally advanced non-metastatic head and neck cancer. Methods: A systematic search of the literature was conducted using Medline, Embase and Cochrane databases and relevant references were included. Results: Literature search revealed a wide variation in dose fractionation regimens. Reported outcomes showed high efficacy and low rate of significant side effects, except in studies utilising higher doses of radiotherapy where higher grade toxicities were seen. Reported median overall survival was in the range of 3.3–17?months, but most studies reported median survival of around 6?months. Conclusions: The choice of palliative radiotherapy varies significantly. This is in contrast to regimens of curative radiotherapy for locally advanced head and neck cancer, which are well standardised. Given the reported relatively short overall survival of this patient group, an ideal treatment should be of the shortest possible duration whilst ensuring effective palliation and minimal side effects. Future well designed trials are needed to evaluate quality of life and duration of side effects in addition to survival and severity of toxicities in this group of patients.     

Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved dose distributions

PURPOSE: To assess the prevalence and dosimetric and clinical predictors of mandibular osteoradionecrosis (ORN) in patients with head and neck cancer who underwent a pretherapy dental evaluation and prophylactic treatment according to a uniform policy and were treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between 1996 and 2005, all patients with head-and-neck cancer treated with parotid gland-sparing IMRT in prospective studies underwent a dental examination and prophylactic treatment according to a uniform policy that included extractions of high-risk, periodontally involved, and nonrestorable teeth in parts of the mandible expected to receive high radiation doses, fluoride supplements, and the placement of guards aiming to reduce electron backscatter off metal teeth restorations. The IMRT plans included dose constraints for the maximal mandibular doses and reduced mean parotid gland and noninvolved oral cavity doses. A retrospective analysis of Grade 2 or worse (clinical) ORN was performed. RESULTS: A total of 176 patients had a minimal follow-up of 6 months. Of these, 31 (17%) had undergone teeth extractions before RT and 13 (7%) after RT. Of the 176 patients, 75% and 50% had received >or=65 Gy and >or=70 Gy to >or=1% of the mandibular volume, respectively. Falloff across the mandible characterized the dose distributions: the average gradient (in the axial plane containing the maximal mandibular dose) was 11 Gy (range, 1-27 Gy; median, 8 Gy). At a median follow-up of 34 months, no cases of ORN had developed (95% confidence interval, 0-2%). CONCLUSION: The use of a strict prophylactic dental care policy and IMRT resulted in no case of clinical ORN. In addition to the dosimetric advantages offered by IMRT, meticulous dental prophylactic care is likely an essential factor in reducing ORN risk.