Bhishamjit S. Chera

DOSIMETRIC COMPARISON OF THREE DIFFERENT INVOLVED NODAL IRRADIATION TECHNIQUES FOR STAGE II HODGKIN'S LYMPHOMA PATIENTS: CONVENTIONAL RADIOTHERAPY, INTENSITY-MODULATED RADIOTHERAPY, AND THREE-DIMENSIONAL PROTON RADIOTHERAPY

PURPOSE To compare the dose distribution to targeted and nontargeted tissues in Hodgkins lymphoma patients using conventional radiotherapy (CRT), intensity-modulated RT (IMRT), and three-dimensional proton RT (3D-PRT). METHODS AND MATERIALS CRT, IMRT, and 3D-PRT treatment plans delivering 30 cobalt Gray equivalent (CGE)/Gy to an involved nodal field were created for 9 Stage II Hodgkins lymphoma patients (n = 27 plans). The dosimetric endpoints were compared. RESULTS The planning target volume was adequately treated using all three techniques. The IMRT plan produced the most conformal high-dose distribution; however, the 3D-PRT plan delivered the lowest mean dose to nontarget tissues, including the breast, lung, and total body. The relative reduction in the absolute lung volume receiving doses of 4-16 CGE/Gy for 3D-PRT compared with CRT ranged from 26% to 37% (p < .05), and the relative reduction in the absolute lung volume receiving doses of 4-10 CGE/Gy for 3D-PRT compared with IMRT was 48-65% (p < .05). The relative reduction in absolute total body volume receiving 4-30 CGE/Gy for 3D-PRT compared with CRT was 47% (p < .05). The relative reduction in absolute total body volume receiving a dose of 4 CGE/Gy for 3D-PRT compared with IMRT was 63% (p = .03). The mean dose to the breast was significantly less for 3D-PRT than for either IMRT or CRT (p = .03) The mean dose and absolute volume receiving 4-30 CGE/Gy for the heart, thyroid, and salivary glands were similar for the three modalities. CONCLUSION In this favorable subset of Hodgkins lymphoma patients without disease in or below the hila, 3D-PRT significantly reduced the dose to the breast, lung, and total body. These observed dosimetric advantages might improve the clinical outcomes of Hodgkins lymphoma patients by reducing the risk of late radiation effects related to low-to-moderate doses in nontargeted tissues.

T1N0 TO T2N0 SQUAMOUS CELL CARCINOMA OF THE GLOTTIC LARYNX TREATED WITH DEFINITIVE RADIOTHERAPY

PURPOSE To report the treatment outcomes of definitive radiotherapy (RT) for early-stage squamous cell carcinoma (SCCA) of the glottic larynx. METHODS AND MATERIALS We retrospectively reviewed the medical records of 585 patients with T1N0 to T2N0 invasive SCCA of the glottic larynx treated between 1964 and 2006 with RT alone. All patients had at least 2 years of follow-up, had histologic diagnosis of invasive SCCA, and received continuous-course RT. None of these patients received chemotherapy or had elective nodal RT. The probabilities of local control (LC), ultimate LC, ultimate LC with larynx preservation, neck control, cause-specific survival (CSS), and overall survival (OS) were calculated by the Kaplan-Meier product-limit method. RESULTS The median follow-up for survivors was 12 years. Five-year LC rates were as follows: T1A, 94%; T1B, 93%; T2A, 80%; and T2B, 70%. Multivariate analysis revealed that overall treatment time greater than 41 days (p = 0.001) and poorly differentiated histology (p = 0.016) adversely affected LC. Five-year rates of ultimate LC with laryngeal preservation were: T1A, 95%; T1B, 94%, T2A, 81%; and T2B, 74%. Twenty-four (4%) of 585 patients failed in the neck; only 7 neck failures (1%) were isolated. Five-year CSS and OS rates were as follows: T1A, 97% and 82%; T1B, 99% and 83%; T2A, 94% and 76%; and T2B, 90% and 78%, respectively. Ten (1.7%) patients had severe and/or fatal complications. One patient died of a radiation-induced carotid artery angiosarcoma. CONCLUSION Based on our study results, RT cures a high proportion of patients with T1N0 to T2N0 glottic SCCAs and has a low rate of severe complications.

Phase 2 Trial of De-intensified Chemoradiation Therapy for Favorable-Risk Human Papillomavirus–Associated Oropharyngeal Squamous Cell Carcinoma

PURPOSE To perform a prospective, multi-institutional, phase 2 study of a substantial decrease in concurrent chemoradiation therapy (CRT) intensity as primary treatment for favorable-risk, human papillomavirus-associated oropharyngeal squamous cell carcinoma. METHODS AND MATERIALS The major inclusion criteria were: (1) T0 to T3, N0 to N2c, M0; (2) human papillomavirus or p16 positive; and (3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiation therapy with concurrent weekly intravenous cisplatinum (30 mg/m(2)). The primary study endpoint was pathologic complete response (pCR) rate based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless of radiographic response. Power computations were performed for the null hypothesis that the pCR rate is 87% and n=40, resulting in a type 1 error of 14.2%. Secondary endpoint measures included physician-reported toxicity (Common Toxicity Terminology for Adverse Events, CTCAE), patient-reported symptoms (PRO-CTCAE), and modified barium swallow studies. RESULTS The study population was 43 patients. The pCR rate was 86% (37 of 43). The incidence of CTCAE grade 3/4 toxicity and PRO-CTCAE severe/very severe symptoms was as follows: mucositis 34%/45%, general pain 5%/48%, nausea 18%/52%, vomiting 5%/34%, dysphagia 39%/55%, and xerostomia 2%/75%. Grade 3/4 hematologic toxicities were 11%. Thirty-nine percent of patients required a feeding tube for a median of 15 weeks (range, 5-22 weeks). There were no significant differences in modified barium swallow studies before and after CRT. CONCLUSIONS The pCR rate with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatinum is very high in favorable-risk oropharyngeal squamous cell carcinoma, with evidence of decreased toxicity compared with standard therapies. ClinicalTrials.gov ID: NCT01530997.

Modeling the dosimetry of organ-at-risk in head and neck IMRT planning: An intertechnique and interinstitutional study

PURPOSE To build a statistical model to quantitatively correlate the anatomic features of structures and the corresponding dose-volume histogram (DVH) of head and neck (HN) Tomotherapy (Tomo) plans. To study if the model built upon one intensity modulated radiation therapy (IMRT) technique (such as conventional Linac) can be used to predict anticipated organs-at-risk (OAR) DVH of patients treated with a different IMRT technique (such as Tomo). To study if the model built upon the clinical experience of one institution can be used to aid IMRT planning for another institution. METHODS Forty-four Tomotherapy intensity modulate radiotherapy plans of HN cases (Tomo-IMRT) from Institution A were included in the study. A different patient group of 53 HN fixed gantry IMRT (FG-IMRT) plans was selected from Institution B. The analyzed OARs included the parotid, larynx, spinal cord, brainstem, and submandibular gland. Two major groups of anatomical features were considered: the volumetric information and the spatial information. The volume information includes the volume of target, OAR, and overlapped volume between target and OAR. The spatial information of OARs relative to PTVs was represented by the distance-to-target histogram (DTH). Important anatomical and dosimetric features were extracted from DTH and DVH by principal component analysis. Two regression models, one for Tomotherapy plan and one for IMRT plan, were built independently. The accuracy of intratreatment-modality model prediction was validated by a leave one out cross-validation method. The intertechnique and interinstitution validations were performed by using the FG-IMRT model to predict the OAR dosimetry of Tomo-IMRT plans. The dosimetry of OARs, under the same and different institutional preferences, was analyzed to examine the correlation between the model prediction and planning protocol. RESULTS Significant patient anatomical factors contributing to OAR dose sparing in HN Tomotherapy plans have been analyzed and identified. For all the OARs, the discrepancies of dose indices between the model predicted values and the actual plan values were within 2.1%. Similar results were obtained from the modeling of FG-IMRT plans. The parotid gland was spared in a comparable fashion during the treatment planning of two institutions. The model based on FG-IMRT plans was found to predict the median dose of the parotid of Tomotherapy plans quite well, with a mean error of 2.6%. Predictions from the FG-IMRT model suggested the median dose of the larynx, median dose of the brainstem and D2 of the brainstem could be reduced by 10.5%, 12.8%, and 20.4%, respectively, in the Tomo-IMRT plans. This was found to be correlated to the institutional differences in OAR constraint settings. Re-planning of six Tomotherapy patients confirmed the potential of optimization improvement predicted by the FG-IMRT model was correct. CONCLUSIONS The authors established a mathematical model to correlate the anatomical features and dosimetric indexes of OARs of HN patients in Tomotherapy plans. The model can be used for the setup of patient-specific OAR dose sparing goals and quality control of planning results.The institutional clinical experience was incorporated into the model which allows the model from one institution to generate a reference plan for another institution, or another IMRT technique.

Carotid-Sparing Intensity-Modulated Radiotherapy for Early-Stage Squamous Cell Carcinoma of the True Vocal Cord

PURPOSE To compare radiation doses to carotid arteries among various radiotherapy techniques for treatment of early-stage squamous cell carcinoma (SCC) of the true vocal cords. METHODS AND MATERIALS Five patients were simulated using computed tomography (CT). Clinical and planning target volumes (PTV) were created for bilateral and unilateral stage T1 vocal cord cancers. Planning risk volumes for the carotid arteries and spinal cord were delineated. For each patient, three treatment plans were designed for bilateral and unilateral target volumes: opposed laterals (LATS), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT), for a total of 30 plans. More than 95% of the PTV received the prescription dose (63Gy at 2.25 Gy per treatment). RESULTS Carotid dose was lowest with IMRT. With a bilateral vocal cord target, the median carotid dose was 10Gy with IMRT vs. 25 Gy with 3DCRT and 38 Gy with LATS (p < 0.05); with a unilateral target, the median carotid dose was 4 Gy with IMRT vs. 19 Gy with 3DCRT and 39 Gy with LATS (p < 0.05). The dosimetric tradeoff with IMRT is a small area of high dose in the PTV. The worst heterogeneity results were at a maximum point dose of 80 Gy (127%) in a unilateral target that was close to the carotid. CONCLUSIONS There is no question that IMRT can reduce the dose to the carotid arteries in patients with early-stage vocal cord cancer. The question is whether the potential advantage of reducing the carotid dose outweighs the risk of tumor recurrence due to contouring errors and organ motion and the risk of complications from dose heterogeneity.

Treatment of Older Patients With Head and Neck Cancer: A Review

The incidence of head and neck cancer (HNC) in the elderly is increasing. The treatment of HNC often includes multimodality therapy that can be quite morbid. Older patients (herein, defined as ≥65 years) with HNC often have significant comorbidity and impaired functional status that may hinder their ability to receive and tolerate combined modality therapy. They have often been excluded from clinical trials that have defined standards of care. Therefore, tailoring cancer therapy for older patients with HNC can be quite challenging. In this paper, we performed a comprehensive literature review to better understand and discuss issues related to therapeutic recommendations that are particular to patients 65 years and older. Evidence suggests that older patients have similar survival outcomes compared with their younger peers; however, they may experience worse toxicity, especially with treatment intensification. Similarly, older patients may require more supportive care throughout the treatment process. Future studies incorporating geriatric tools for predictive and interventional purposes will potentially allow for improved patient selection and tolerance to intensive treatment.

A radiation oncologist's guide to contouring the hippocampus.

Objectives:Limiting the dose to the hippocampus will likely decrease cognitive problems from brain radiotherapy. The purpose of this article is to present a step-by-step guide to contouring the hippocampus on axial images as would be done in the standard process of planning conformal radiotherapy for brain radiotherapy. Materials and Methods:We explain how to contour the hippocampus on axial T1 echo sequence magnetic resonance images with intravenous gadolinium. Results:Step 1: Find the slice where the temporal horn—meaning the most anterior portion of the lateral ventricle—is well visualized; the hippocampus is the gray matter inside the curve of the temporal horn. Step 2: Contour inferiorly from the level of the temporal horn; below the level of temporal horn there is no visible boundary between the hippocampus and amygdala. You have to guess where this boundary is by extrapolating from more superior slices. The caudal most portion of the hippocampus is at the level of the pons and pituitary gland. Step 3: Contour superiorly from the level of the temporal horn; above the level of the temporal horn the hippocampus is the strip of gray matter bounded by cerebrospinal fluid in the lateral ventricle and ambient cistern. The cranial-most extent of the hippocampus is at the level of the splenium of the corpus callosum. Conclusions:This article presents a step-by-step guide to contouring the hippocampus on axial magnetic resonance images for radiation therapy treatment planning.

High XRCC1 Protein Expression Is Associated with Poorer Survival in Patients with Head and Neck Squamous Cell Carcinoma

Purpose: We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome. Experimental Design: XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1). Results: Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44–8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16INK4a-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52–4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06–0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36–15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08–0.92, respectively; P = 0.037). Conclusions: In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment. Clin Cancer Res; 17(20); 6542–52. ©2011 AACR.

Different cellular p16 INK4a localisation may signal different survival outcomes in head and neck cancer

Background:Recently, the management of head and neck squamous cell carcinoma (HNSCC) has focused considerable attention on biomarkers, which may influence outcomes. Tests for human papilloma infection, including direct assessment of the virus as well as an associated tumour suppressor gene p16, are considered reproducible. Tumours from familial melanoma syndromes have suggested that nuclear localisation of p16 might have a further role in risk stratification. We hypothesised p16 staining that considered nuclear localisation might be informative for predicting outcomes in a broader set of HNSCC tumours not limited to the oropharynx, human papilloma virus (HPV) status or by smoking status.Methods:Patients treated for HNSCC from 2002 to 2006 at UNC (University of North Carolina at Chapel Hill) hospitals that had banked tissue available were eligible for this study. Tissue microarrays (TMA) were generated in triplicate. Immunohistochemical (IHC) staining for p16 was performed and scored separately for nuclear and cytoplasmic staining. Human papilloma virus staining was also carried out using monoclonal antibody E6H4. p16 expression, HPV status and other clinical features were correlated with progression-free (PFS) and overall survival (OS).Results:A total of 135 patients had sufficient sample for this analysis. Median age at diagnosis was 57 years (range 20–82), with 68.9% males, 8.9% never smokers and 32.6% never drinkers. Three-year OS rate and PFS rate was 63.0% and 54.1%, respectively. Based on the p16 staining score, patients were divided into three groups: high nuclear, high cytoplasmic staining group (HN), low nuclear, low cytoplasmic staining group (LS) and high cytoplasmic, low nuclear staining group (HC). The HN and the LS groups had significantly better OS than the HC group with hazard ratios of 0.10 and 0.37, respectively, after controlling for other factors, including HPV status. These two groups also had significantly better PFS than the HC staining group. This finding was consistent for sites outside the oropharynx and did not require adjustment for smoking status.Conclusion:Different p16 protein localisation suggested different survival outcomes in a manner that does not require limiting the biomarker to the oropharynx and does not require assessment of smoking status.

Proton therapy for maxillary sinus carcinoma.

Objectives:To compare the dose-volume data of three-dimensional conformal proton therapy (3DCPT) versus intensity-modulated radiotherapy (IMRT) for a paranasal sinus malignancy. Methods:3DCPT and IMRT plans were created for a T4N0 maxillary sinus carcinoma. Results:The target volume dose distributions were comparable for 3DCPT and IMRT. The mean and integral doses for all normal tissues were lower for 3DCPT. The maximum doses for both plans to the ipsilateral optic nerve/retina/lens, temporal lobe, pituitary, and brain exceeded tolerance doses. The contralateral parotid, lacrimal gland, and lens were avoided with 3DCPT. Neither 3DCPT nor IMRT exceeded the maximal tolerated dose for the brainstem, optic chiasm, contralateral temporal lobe, parotid, or lacrimal gland. Conclusions:Both 3DCPT and IMRT sufficiently covered the target volume(s). Although 3DCPT reduced the mean and integral dose to all of the normal tissues, both 3DCPT and IMRT irradiated the ipsilateral optic structures beyond acceptable tolerance doses.