Clinical application of intensity-modulated radiotherapy for head and neck cancer

Intensity-modulated radiotherapy (IMRT) is a modern treatment technique that allows one to shape the dose to the target volume and to reduce the dose delivered to healthy tissue. Over the last decade, IMRT has been implemented for head and neck cancer treatment, with the aim of reducing the dose delivered to the parotid glands and improving the dose coverage of complex target volumes located close to critical structures. The potential benefits of IMRT in terms of salivary function preservation and better local control have contributed to the rapid diffusion of this new technology. However, it should not be overlooked that IMRT is a novel treatment technique and that its clinical application represents a paradigm shift in the practice of radiation oncology. The purpose of this article is to review the clinical experience with IMRT for head and neck cancer treatment and to discuss some important issues related to its implementation.     

Recurrence in region of spared parotid gland after definitive intensity-modulated radiotherapy for head and neck cancer

PURPOSE: To discuss the implications of three examples of periparotid recurrence after definitive intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC). METHODS AND MATERIALS: We present 3 patients with HNC who underwent definitive IMRT with concurrent chemotherapy and later had treatment failure in or near a spared parotid gland. Two patients had bilateral multilevel nodal disease, and all had Level II nodal disease ipsilateral to the site of recurrence. The patients were treated using dose-painting IMRT with a dose of 70 Gy to the gross tumor volume and 59.4 Gy or 54 Gy to the high-risk or low-risk clinical tumor volume, respectively. The parotid glands were spared bilaterally. The patients had not undergone any surgical treatment for HNC before radiotherapy. RESULTS: All patients had treatment failure in the region of a spared parotid gland. Failure in the 2 patients with bilateral multilevel nodal involvement occurred in the periparotid lymph nodes. The third patient developed a dermal metastasis near the tail of a spared parotid gland. On pretreatment imaging, the 2 patients with nodal failure had small nonspecific periparotid nodules that showed no hypermetabolic activity on positron emission tomography. CONCLUSION: For HNC patients receiving definitive IMRT, nonspecific positron emission tomography-negative periparotid nodules on pretreatment imaging should raise the index of suspicion for subclinical disease in the presence of multilevel or Level II nodal metastases. Additional evaluation of such nodules might be indicated before sparing the ipsilateral parotid gland.     

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.     

Evidence-based review: Quality of life following head and neck intensity-modulated radiotherapy

Inverse planned Intensity modulated radiotherapy (IMRT) can minimize the dose to normal structures and therefore can reduce long-term radiotherapy-related morbidity and may improve patients’ long-term quality of life. Despite overwhelming evidence that IMRT can reduce late functional deficits in patients with head and neck cancer, treated with radiotherapy, a review of the published literature produced conflicting results with regard to quality of life outcomes. Following a critical appraisal of the literature, reasons for the discrepant outcomes are proposed.     

Impact of intensity-modulated radiotherapy on health-related quality of life for head and neck cancer patients: matched-pair comparison with conventional radiotherapy

PURPOSE: To assess the benefit of intensity-modulated radiotherapy (IMRT) compared with conventional RT for the quality of life (QOL) of head and neck cancer survivors. METHODS AND MATERIALS: Cross-sectional QOL measures (European Organization for Research and Treatment of Cancer QOL questionnaire C30 and head and neck cancer module) were used with a French multicenter cohort of patients cured of head and neck cancer (follow-up > or = 1 year) who had received bilateral neck RT (> or = 45 Gy) as a part of their initial treatment. We compared the QOL mean scores regarding RT modality (conventional RT vs. IMRT). The patients of the two groups were matched (one to one) according to the delay between the end of RT and the timing of the QOL evaluation and the T stage. Each QOL item was divided into two relevant levels of severity: "not severe" (responses, "not at all" and "a little") vs. "severe" (responses "quite a bit" and "very much"). The association between the type of RT and the prevalence of severe symptoms was approximated, through multivariate analysis using the prevalence odds ratio. RESULTS: Two comparable groups (67 pairs) were available. Better scores were observed on the head and neck cancer module QOL questionnaire for the IMRT group, especially for dry mouth and sticky saliva (p < 0.0001). Severe symptoms were more frequent with conventional RT concerning saliva modifications and oral discomfort. The adjusted prevalence odds ratios were 3.17 (p = 0.04) for dry mouth, 3.16 (p = 0.02) for sticky saliva, 3.58 (p = 0.02) for pain in the mouth, 3.35 (p = 0.04) for pain in the jaw, 2.60 (p = 0.02) for difficulties opening the mouth, 2.76 (p = 0.02) for difficulties with swallowing, and 2.68 (p = 0.03) for trouble with eating. CONCLUSION: The QOL assessment of head and neck cancer survivors demonstrated the benefit of IMRT, particularly in the areas of salivary dysfunction and oral discomfort.     

Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer

PURPOSE: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. METHODS AND MATERIALS: A Phase I clinical trial was designed to escalate the dose limited to the [(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was applied for the remaining 22 fractions of 2.16 Gy. RESULTS: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p = n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted (18)F-FDG-PET-delineated region. CONCLUSIONS: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.     

Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer

Purpose: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT).

Methods and Materials: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose–volume histograms. The recurrences were classified as 1) “in-field,” in which 95% or more of the recurrence volume (V_recur) was within the 95% isodose; 2) “marginal,” in which 20% to 95% of V_recur was within the 95% isodose; or 3) “outside,” in which less than 20% of V_recur was within the 95% isodose.

Results: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1 stomal recurrence were seen in 12 patients, for a 2-year actuarial local-regional control rate of 79% (95% confidence interval 68–90%). Ten patients (80%) relapsed in-field (in areas of previous gross tumor in nine patients), and two patients developed marginal recurrences in the side of the neck at highest risk (one in the high retropharyngeal nodes/base of skull and one in the submandibular nodes). Four regional recurrences extended superior to the jugulodigastric node, in the high jugular and retropharyngeal nodes near the base of skull of the side of the neck at highest risk. Three of these were in-field, in areas that had received the dose intended for subclinical disease. No recurrences were seen in the nodes superior to the jugulodigastric nodes in the side of the neck at less risk, where RT was partially spared.

Conclusions: The majority of local-regional recurrences after conformal and segmental IMRT were “in-field,” in areas judged to be at high risk at the time of RT planning, including the GTV, the operative bed, and the first echelon nodes. These findings motivate studies of dose escalation to the highest risk regions.     

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.     

Intensity-modulated radiotherapy for head and neck cancer of unknown primary: toxicity and preliminary efficacy

PURPOSE: Unknown primary head and neck cancers often require comprehensive mucosal and bilateral neck irradiation. With conventional techniques, significant toxicity can develop. Intensity-modulated radiotherapy (IMRT) has the potential to minimize the toxicity. METHODS AND MATERIALS: Between 2000 and 2005, 21 patients underwent IMRT for unknown primary head and neck cancer at our center. Of the 21 patients, 5 received IMRT with definitive intent and 16 as postoperative therapy; 14 received concurrent chemotherapy and 7 IMRT alone. The target volumes included the bilateral neck and mucosal surface. The median dose was 66 Gy. Acute and chronic toxicities, esophageal strictures, and percutaneous endoscopic gastrostomy tube dependence were evaluated. Progression-free survival, regional progression-free survival, distant metastasis-free survival, and overall survival were estimated with Kaplan-Meier curves. RESULTS: With a median follow-up of 24 months, the 2-year regional progression-free survival, distant metastasis-free survival, and overall survival rate was 90%, 90%, and 85%, respectively. Acute grade 1 and 2 xerostomia was seen in 57% and 43% of patients, respectively. Salivary function improved with time. Percutaneous endoscopic gastrostomy tube placement was required in 72% with combined modality treatment and 43% with IMRT alone. Only 1 patient required percutaneous endoscopic gastrostomy support at the last follow-up visit. Two patients treated with combined modality and one treated with IMRT alone developed esophageal strictures, but all had improvement or resolution with dilation. CONCLUSION: The preliminary analysis of IMRT for unknown primary head and neck cancer has shown acceptable toxicity and encouraging efficacy. The analysis of the dosimetric variables showed excellent tumor coverage and acceptable doses to critical normal structures. Esophageal strictures developed but were effectively treated with dilation. Techniques to limit the esophageal dose could help further minimize this complication.     

Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer

Background and purpose

Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN.

Materials and methods

Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n = 40 plans) and dose-volume histograms were generated.

Results

The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p = 0.020) and mean doses to the contralateral parotid gland (p = 0.049) and larynx (p = 0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lowered the maximum doses to the spinal cord (p < 0.002 for both) and brainstem (p < 0.002 for both) and mean doses to the larynx (p < 0.002 for both) and ipsilateral (p = 0.004 IMRT, p = 0.050 adaptive) and contralateral (p < 0.002 IMRT, p = 0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT.

Conclusions

Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage.     

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.     

Treatment of late sequelae after radiotherapy for head and neck cancer

Radiotherapy (RT) is used to treat approximately 80% of patients with cancer of the head and neck. Despite enormous advances in RT planning and delivery, a significant number of patients will experience radiation-associated toxicities, especially those treated with concurrent systemic agents. Many effective management options are available for acute RT-associated toxicities, but treatment options are much more limited and of variable benefit among patients who develop late sequelae after RT. The adverse impact of developing late tissue damage in irradiated patients may range from bothersome symptoms that negatively affect their quality of life to severe life-threatening complications. In the region of the head and neck, among the most problematic late effects are impaired function of the salivary glands and swallowing apparatus. Other tissues and structures in the region may be at risk, depending mainly on the location of the irradiated tumor relative to the mandible and hearing apparatus. Here, we review the available evidence on the use of different therapeutic strategies to alleviate common late sequelae of RT in head and neck cancer patients, with a focus on the critical assessment of the treatment options for xerostomia, dysphagia, mandibular osteoradionecrosis, trismus, and hearing loss.     

The role of split-course hypofractionated palliative radiotherapy in head and neck cancer

Aims

A significant proportion of patients with head and neck squamous cell carcinoma are unsuitable for radical treatment due to factors including tumour stage, performance status and co-morbidity. Palliative radiotherapy has a useful role in the control of local symptoms. This study documented the outcome with split-course hypofractionated radiotherapy.

Materials and methods

Thirty-three previously untreated patients with head and neck squamous cell carcinoma were treated with palliative intent with split-course radiotherapy, with an initial 20 Gy in five fractions over 1 week, a 2 week gap, and then a further 20 Gy in five fractions over 1 week at the Yorkshire Cancer Centre between January 2004 and December 2007. Data were collected retrospectively from case notes and radiotherapy records.

Results

Thirty (91%) patients had stage IV A-B disease. World Health Organization performance status was 2 or 3 in 19 (58%) patients. The median age was 76 years (range 48-91 years). Twenty-five (76%) patients were men. Symptomatic improvement was reported in 26 (79%) patients at 4-6 weeks of follow-up. Thirteen (39%) patients had a complete tumour response and 11 (33%) patients had a partial response as assessed clinically, and in some cases radiologically. The median overall survival was 9 months (range 3-43 months). Progression-free survival at 1 and 2 years was 35 and 25%, respectively. Overall survival at 1 and 2 years was 42 and 34%, respectively. Treatment was generally well tolerated; admission for nasogastric feeding and/or supportive care was required in only six patients. Radiation Therapy Oncology Group grade 3 toxicity was documented for skin in one patient, for mucosa in two patients and for oesophagitis in three patients.

Conclusion

Split-course hypofractionated radiotherapy is an effective palliative regimen with acceptable toxicity.     

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.     

Patterns of failure after combined-modality approaches incorporating radiotherapy for sinonasal undifferentiated carcinoma of the head and neck

PURPOSE: To report the clinical outcome of patients treated with combined-modality approaches for sinonasal undifferentiated carcinoma (SNUC) of the head and neck. METHODS AND MATERIALS: The records of 21 patients with SNUC treated with curative intent at the University of California, San Francisco between 1990 and 2004 were analyzed. Patient age ranged from 33 to 71 years (median, 47 years). Primary tumor sites included the nasal cavity (11 patients), maxillary sinus (5 patients), and ethmoid sinus (5 patients). All patients had T3 (4 patients) or T4 (17 patients) tumors. Local-regional treatment included surgery followed by postoperative radiotherapy (PORT) with or without adjuvant chemotherapy for 17 patients; neoadjuvant chemoradiotherapy followed by surgery for 2 patients; and definitive chemoradiotherapy for 2 patients. Median follow-up among surviving patients was 58 months (range, 12-70 months). RESULTS: The 2- and 5-year estimates of local control were 60% and 56%, respectively. There was no difference in local control according to initial treatment approach, but among the 19 patients who underwent surgery the 5-year local control rate was 74% for those with gross tumor resection, compared with 24% for those with subtotal tumor resection (p = 0.001). The 5-year rates of overall and distant metastasis-free survival were 43% and 64%, respectively. Late complications included cataracts (2 patients), lacrimal stenosis (1 patient), and sino-cutaneous fistula (1 patient). CONCLUSION: The suboptimal outcomes suggest a need for more effective therapies. Gross total resection should be the goal of all treatments whenever possible.     

Concomitant boost radiotherapy for advanced squamous cell carcinoma of the head and neck

The concomitant boost technique is a variant of accelerated fractionation whereby the boost is delivered as a second daily fraction during the basic treatment course to reduce the total duration of treatment. From April 1972 through June 1983, 53 patients with advanced squamous cell carcinoma of various sites in the head and neck region were treated for cure at U.T. M. D. Anderson Hospital with this technique. In 12 patients, the concomitant boost was used because of rapid recurrence following surgical resection either before or after initiation of planned postoperative radiotherapy; the remaining patients had rapidly growing untreated or recurrent disease in the primary site, neck, or both. In most cases, the concomitant boost was delivered in fractions of 120-150 cGy, separated by 3-6 h from the basic daily treatment of 180-200 cGy. The boost treatments were given 2-3 times a week for 3-5 weeks, delivering an average of about 17 Gy in 12 fractions. Two different treatment techniques were used. Patients with predominantly neck disease (30) were treated with glancing AP and PA fields or with appositional electron beam portals to spare the mucous membranes, while those with advanced or rapidly progressive primary lesions, with or without nodal disease (23), received their concomitant boost through lateral photon or high energy electron beams to include the primary tumor site. As expected, the acute mucosal reactions were most severe in the latter group, but only three patients required interruption of treatment because of severe mucositis.(ABSTRACT TRUNCATED AT 250 WORDS)