Swallowing-sparing intensity-modulated radiotherapy for head and neck cancer patients: Treatment planning optimization and clinical introduction

Purpose

To report on the potential benefits of swallowing-sparing intensity-modulated radiation therapy (SW-IMRT) in the first 100 SW-IMRT treated patients, as well as on the factors that influence the potential benefit of SW-IMRT relative to standard parotid sparing (ST)-IMRT.

Material and methods

One hundred consecutive head and neck cancer patients, scheduled for primary radiotherapy, were included in this prospective cohort study. For each patient, ST-IMRT and SW-IMRT treatment plans were created. All patients were eventually treated with SW-IMRT. Objectives for SW-IMRT were identical to those with ST-IMRT, with additional objectives to spare the swallowing organs at risk (SWOARs). After 20 patients, interim results were evaluated by a multidisciplinary committee.

Results

The mean gain of SW-IMRT relative to ST-IMRT in the first 20 patients was less than expected based on our previous planning comparative study. A critical review of all plans revealed that the results with SW-IMRT could be improved by: (1) gaining experience and attempting to reduce SWOAR dose as much as possible; (2) accepting a moderate shift of dose to unspecified tissues; (3) maximizing SWOAR sparing while keeping PTV coverage exactly according to protocol. In the additional 80 patients, the mean dose to the various SWOARs was further reduced significantly compared to ST-IMRT. Dose reductions with SW-IMRT were largest for patients who received neck irradiation, had a tumour located in the larynx, oropharynx, nasopharynx or oral cavity, and had <75% overlap between SWOARs and PTVs. The mean absolute reduction in predicted physician-rated RTOG grade 2–4 swallowing dysfunction for patients numbered 21–100 was 6.1%, ranging from 0.0% to 17.2%.

Conclusions

The benefit of SW-IMRT depends significantly on neck radiotherapy, tumour site and the amount of overlap between SWOARs and PTVs. Optimal clinical introduction requires a detailed evaluation and comparison between the standard (ST-IMRT) and new technique (SW-IMRT) in order to fully exploit the potential benefits.     

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.     

Intensity-modulated radiotherapy of head and neck cancer aiming to reduce dysphagia: early dose-effect relationships for the swallowing structures

PURPOSE: To present initial results of a clinical trial of intensity-modulated radiotherapy (IMRT) aiming to spare the swallowing structures whose dysfunction after chemoradiation is a likely cause of dysphagia and aspiration, without compromising target doses. METHODS AND MATERIALS: This was a prospective, longitudinal study of 36 patients with Stage III-IV oropharyngeal (31) or nasopharyngeal (5) cancer. Definitive chemo-IMRT spared salivary glands and swallowing structures: pharyngeal constrictors (PC), glottic and supraglottic larynx (GSL), and esophagus. Lateral but not medial retropharyngeal nodes were considered at risk. Dysphagia endpoints included objective swallowing dysfunction (videofluoroscopy), and both patient-reported and observer-rated scores. Correlations between doses and changes in these endpoints from pre-therapy to 3 months after therapy were assessed. RESULTS: Significant correlations were observed between videofluoroscopy-based aspirations and the mean doses to the PC and GSL, as well as the partial volumes of these structures receiving 50-65 Gy; the highest correlations were associated with doses to the superior PC (p = 0.005). All patients with aspirations received mean PC doses >60 Gy or PC V(65) >50%, and GSL V(50) >50%. Reduced laryngeal elevation and epiglottic inversion were correlated with mean PC and GSL doses (p < 0.01). All 3 patients with strictures had PC V(70) >50%. Worsening patient-reported liquid swallowing was correlated with mean PC (p = 0.05) and esophageal (p = 0.02) doses. Only mean PC doses were correlated with worsening patient-reported solid swallowing (p = 0.04) and observer-rated swallowing scores (p = 0.04). CONCLUSIONS: These dose-volume-effect relationships provide initial IMRT optimization goals and motivate further efforts to reduce swallowing structures doses to reduce dysphagia and aspiration.     

Use of external beam radiotherapy is associated with reduced incidence of second primary head and neck cancer: a SEER database analysis

PURPOSE: Patients with head and neck cancer have a significant risk of developing a second primary cancer of the head and neck. We hypothesized that treatment with external beam radiotherapy (RT) might reduce this risk, because RT can eradicate occult foci of second head and neck cancer (HNCA). METHODS AND MATERIALS: The data of patients with Surveillance, Epidemiology, and End Results Historic Stage A localized squamous cell carcinoma of the oral cavity, larynx, and pharynx were queried using the Surveillance, Epidemiology, and End Results database. For patients treated with or without RT, the incidence of second HNCA was determined and compared using the log-rank method. Cox proportional hazards analysis was performed for each site, evaluating the influence of covariates on the risk of second HNCA. RESULTS: Between 1973 and 1997, 27,985 patients were entered with localized HNCA. Of these patients, 44% had received RT and 56% had not. The 15-year incidence of second HNCA was 7.7% with RT vs. 10.5% without RT (hazard ratio 0.71, p <0.0001). The effect of RT was more profound in patients diagnosed between 1988 and 1997 (hazard ratio 0.53, p <0.0001) and those with pharynx primaries (hazard ratio 0.47, p <0.0001). On multivariate analysis, RT was associated with a reduced risk of second HNCA for pharynx (p <0.0001) and larynx (p = 0.04) tumors. For oral cavity primaries, RT was associated with an increased risk of second HNCA in patients treated before 1988 (p <0.001), but had no influence on patients treated between 1988 and 1997 (p = 0.91). CONCLUSION: For localized HNCA, RT is associated with a reduced incidence of second HNCA. These observations are consistent with the eradication of microscopic foci of second HNCA with external beam RT.     

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).     

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.     

A dose escalation study of hyperfractionated accelerated radiation delivered with integrated neck surgery (HARDWINS) for the management of advanced head and neck cancer

BACKGROUND AND PURPOSE: To determine toxicity and outcome of radiation dose escalation with hyperfractionated accelerated radiation delivered with neck surgery (HARDWINS) for head and neck cancer. PATIENTS AND METHODS: Patients with stage III and IV squamous cell carcinoma of the oropharynx, hypopharynx or larynx were enrolled. Dose levels of 60, 62 and 64Gy were delivered with twice daily fractionation in 40 fractions over 4 weeks. Involved and at-risk nodal regions received microscopic dose (46.5-48Gy) with neck dissection for node positive patients 8 weeks after radiation. RESULTS: One hundred and sixty-nine patients were enrolled (60Gy n=22, 62Gy n=26, 64Gy n=121). No grade 4 acute toxicity was observed. Incidence of acute grade 3 toxicity was: skin (2%), larynx (6%), pharynx and esophagus (66%) and mucous membrane (75%). Feeding tube dependence was observed in 14% of patients receiving 64Gy. Overall survival, and relapse free rate at 5 years were 65% and 63%, respectively. Local, nodal and distant relapse free rates at 5 years were 77%, 94% and 81% (median follow-up 3.8 years). CONCLUSIONS: HARDWINS can be delivered without acute grade 4 toxicity but significant grade 3 acute toxicity. A significant proportion of the patients have prolonged swallowing dysfunction. Outcomes suggest this regimen represents an alternative to chemoradiation.     

High-dose reirradiation with intensity-modulated radiotherapy for recurrent head-and-neck cancer: Disease control,survival and toxicity

Purpose

To evaluate disease control, survival and severe late toxicity after high-dose fractionated reirradiation using intensity-modulated radiotherapy (IMRT) for recurrent head-and-neck cancer.

Materials and methods

Sixty consecutive patients were reirradiated with IMRT between 1997 and 2011. The median prescribed dose was 70 Gy in 35 daily fractions until 2004 and 69.12 Gy in 32 daily fractions thereafter. The median cumulative dose was 132 Gy. Sixty-seven percent of patients had non-metastatic stage IV disease. Surgery prior to reirradiation and concomitant systemic therapy was performed in 13 (22%) and 20 (33%) patients, respectively.

Results

Median follow-up in living patients was 18.5 months. Actuarial 1-, 2- and 5-year locoregional control was 64%, 48% and 32%, respectively. Median overall (OS) and disease-free survival was 9.6 and 6.7 months, respectively. Actuarial 1-, 2- and 5-year OS was 44%, 32% and 22%, respectively. Seventeen (27%) and 2 (3%) patients had grade 3 and 4 acute toxicity, respectively. Cumulative incidence of late grade ? 3 toxicity was 23%, 27% and 66% at 1, 2 and 5 years, respectively. In 4 patients, death was attributed to toxicity: fatal bleeding (n = 2), aspiration pneumonia (n = 1) and skin necrosis (n = 1).

Conclusions

High-dose fractionated reirradiation with IMRT offers 5-year disease control and OS in recurrent head-and-neck cancer for 1/3 and 1/4 patients, respectively. Severe late toxicity after 1–2 and 5 years occurs in 1/4 and 2/3 patients, respectively.     

Dose to the inferior pharyngeal constrictor predicts prolonged gastrostomy tube dependence with concurrent intensity-modulated radiation therapy and chemotherapy for locally-advanced head and neck cancer

Background and purpose

To determine if dose and/or dose-volume parameters to anatomic swallowing structures are predictive of gastrostomy tube (PEG) dependence from chemotherapy-intensity modulated radiotherapy (IMRT) in locally advanced head and neck cancer (LAHNC).

Methods and materials

A retrospective study was performed on 141 consecutive patients with LAHNC (squamous cell) treated with definitive chemoIMRT with weekly concurrent carboplatin and paclitaxel. Late dysphagia was assessed by length of PEG requirement. Analysis of IMRT dose was retrospectively performed for critical swallowing structures.

Results

Approximately 62% of patients required PEG, the majority placed during treatment. Mean and median time for PEG was 7.7 and 4.4 months respectively (range 1.4–43.8). Only IMRT dose to the inferior constrictor was significantly associated with length of PEG. Mean dose (of individual mean doses) was 47 Gy for prolonged PEG use versus 41 Gy for PEG ?12 months. V₄₀ to the inferior constrictor also correlated with PEG >12 months (p = 0.02) with a mean V₄₀ of 48% versus 41% for PEG ?12 months.

Conclusions

IMRT dose to the inferior constrictor correlated with persistent dysphagia requiring prolonged PEG use. Maintaining mean inferior constrictor dose to ?41 Gy and V₄₀ to ?41% may help minimize gastrostomy tube dependence.     

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.     

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.     

Secondary radiation doses of intensity-modulated radiotherapy and proton beam therapy in patients with lung and liver cancer

Purpose

To compare the secondary radiation doses following intensity-modulated radiotherapy (IMRT) and proton beam therapy (PBT) in patients with lung and liver cancer.

Methods and materials

IMRT and PBT were planned for three lung cancer and three liver cancer patients. The treatment beams were delivered to phantoms and the corresponding secondary doses during irradiation were measured at various points 20-50 cm from the beam isocenter using ion chamber and CR-39 detectors for IMRT and PBT, respectively.

Results

The secondary dose per Gy (i.e., a treatment dose of 1 Gy) from PBT for lung and liver cancer, measured 20-50 cm from the isocenter, ranged from 0.17 to 0.086 mGy. The secondary dose per Gy from IMRT, however, ranged between 5.8 and 1.0 mGy, indicating that PBT is associated with a smaller dose of secondary radiation than IMRT. The internal neutron dose per Gy from PBT for lung and liver cancer, 20-50 cm from the isocenter, ranged from 0.03 to 0.008 mGy.

Conclusions

The secondary dose from PBT is less than or compatible to the secondary dose from conventional IMRT. The internal neutron dose generated by the interaction between protons and body material is generally much less than the external neutron dose from the treatment head.