Hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV) for newly diagnosed glioblastoma multiforme (GBM): a comparison of two prospective phase II trials.

To compare progression-free (PFS) and overall survival (OS) in patients treated in two consecutive phase II trials of hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV). Patients with newly diagnosed glioblastoma multiforme (GBM) after biopsy or resection were enrolled on a clinical trial with hypo-IMRT and TMZ (hypo-IMRT/TMZ alone) from 2008 to 2010, or in the second protocol with the same hypo-IMRT and TMZ plus BEV (hypo-IMRT/TMZ/BEV) from 2010 to 2013. All patients received postoperative hypo-IMRT to the surgical cavity and residual tumor plus margin to a total dose of 60 Gy and to the T2 abnormality with margin to 30 Gy, both in ten fractions. Concurrent TMZ (75 mg/m(2)/day) was given to all patients for 28 consecutive days followed by adjuvant TMZ (150-200 mg/m(2)/day). Patients enrolled on the hypo-IMRT/TMZ/BEV trial received concurrent and adjuvant BEV (10 mg/kg) on days 1 and 15 of each 28-day cycle. Hazard ratios of PFS and OS were compared between trials in a Cox proportional hazards model. Twenty-six patients were enrolled on the hypo-IMRT/TMZ alone trial and 30 patients on the hypo-IMRT/TMZ/BEV trial. Median follow-up was 13.9 and 14.7 months, respectively. Median PFS was 3.4 months longer with hypo-IMRT/TMZ/BEV but the difference was not statistically significant (12.8 vs. 9.4 months, p = 0.58). Median (OS) was 16.3 months for both trials. The addition of BEV to TMZ and hypo-IMRT did not improve OS for patients with GBM in two phase II trials with small patient numbers; PFS was longer with BEV, but the difference was not statistically significant.

Phase II trial of hypofractionated intensity-modulated radiation therapy combined with temozolomide and bevacizumab for patients with newly diagnosed glioblastoma.

Bevacizumab blocks the effects of VEGF and may allow for more aggressive radiotherapy schedules. We evaluated the efficacy and toxicity of hypofractionated intensity-modulated radiation therapy with concurrent and adjuvant temozolomide and bevacizumab in patients with newly diagnosed glioblastoma. Patients with newly diagnosed glioblastoma were treated with hypofractionated intensity modulated radiation therapy to the surgical cavity and residual tumor with a 1 cm margin (PTV1) to 60 Gy and to the T2 abnormality with a 1 cm margin (PTV2) to 30 Gy in 10 daily fractions over 2 weeks. Concurrent temozolomide (75 mg/m(2) daily) and bevacizumab (10 mg/kg) was administered followed by adjuvant temozolomide (200 mg/m(2)) on a standard 5/28 day cycle and bevacizumab (10 mg/kg) every 2 weeks for 6 months. Thirty newly diagnosed patients were treated on study. Median PTV1 volume was 131.1 cm(3) and the median PTV2 volume was 342.6 cm(3). Six-month progression-free survival (PFS) was 90 %, with median follow-up of 15.9 months. The median PFS was 14.3 months, with a median overall survival (OS) of 16.3 months. Grade 4 hematologic toxicity included neutropenia (10 %) and thrombocytopenia (17 %). Grades 3/4 non-hematologic toxicity included fatigue (13 %), wound dehiscence (7 %) and stroke, pulmonary embolism and nausea each in 1 patient. Presumed radiation necrosis with clinical decline was seen in 50 % of patients, two with autopsy documentation. The study was closed early to accrual due to this finding. This study demonstrated 90 % 6-month PFS and OS comparable to historic data in patients receiving standard treatment. Bevacizumab did not prevent radiation necrosis associated with this hypofractionated radiation regimen and large PTV volumes may have contributed to high rates of presumed radiation necrosis.

Determination of optimal PTV margin for patients receiving CBCT-guided prostate IMRT: comparative analysis based on CBCT dose calculation with four different margins.

Variations in daily setup and rectum/bladder filling lead to uncertainties in the delivery of prostate IMRT. The purpose of this study is to determine the optimal PTV margin for CBCT-guided prostate IMRT based on daily CBCT dose calculations using four different margins. Five patients diagnosed with low-risk prostate cancer were treated with prostate IMRT to 70 Gy in 28 fractions using daily CBCT for image guidance. The prostate CTV and OARs were contoured on all CBCTs. IMRT plans were created using 1 mm, 3 mm, 5 mm, and 7 mm CTV to PTV expansions. For each delivered fraction, dose calculations were generated utilizing the pretreatment CBCT translational shifts performed and dosimetric analysis was performed. One hundred and forty total treatment fractions (CBCT sessions) were evaluated. The planned prostate CTV V100% was 100% for all PTV margins. Based on CBCT analysis, the actual cumulative CTVs V100% were 96.55% ± 2.94%, 99.49% ± 1.36%, 99.98% ± 0.26%, and 99.99% ± 0.05% for 1, 3, 5, and 7 mm uniform PTV margins, respectively. Delivered rectum and bladder doses were different as compared to expected planned doses, with the magnitude of differences increasing with PTV margin. Daily setup variation during prostate IMRT yields differences in the actual vs. expected doses received by the prostate CTV, rectum, and bladder. The magnitude of these differences is significantly affected by the PTV margin utilized. It was found that when daily CBCT was used for soft-tissue alignment of the prostate, a 3 mm PTV margin allowed for CTV to be covered for 99% of cases.

Prospective evaluation of health-related quality of life in patients with glioblastoma multiforme treated on a phase II trial of hypofractionated IMRT with temozolomide.

To report health-related quality of life (HRQOL) in glioblastoma (GBM) patients treated on a phase II trial of hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with temozolomide (TMZ). GBM patients received postoperative hypo-IMRT to 60 Gy in 10 fractions with TMZ. HRQOL was assessed using the EORTC quality of life questionnaire core-30 and the EORTC brain cancer module, performed at baseline, RT completion, 1 mo post-RT, and every 3 mos thereafter. Changes from baseline were calculated for each specific HRQOL scale. A ≥ 10 point change in any HRQOL scale from the mean baseline score was significant. 24 patients were treated. Compliance with HRQOL assessments at baseline, RT completion, and 1, 3, 6, 9, and 12 mos post-RT was 100, 96, 92, 79, 70, 68 and 53 %, respectively. Up to 12 mos post-RT, no significant changes were seen in global health status, physical functioning, role functioning, emotional functioning, fatigue, nausea, vision, headache or seizure. Significant improvement was seen in insomnia, future uncertainty, motor dysfunction and drowsiness. Significant worsening was observed in cognitive functioning, social functioning, appetite loss and communication deficit. 60 Gy hypo-IMRT in 6-Gy fractions with TMZ does not appear to negatively impact overall HRQOL.

Survival and patterns of relapse in patients with oral tongue cancer.

PURPOSE: To evaluate the survival and patterns of relapse for patients with squamous cell carcinoma (SCC) of the oral tongue. PATIENTS AND METHODS: Between 1999 and 2007, 50 patients with SCC of the oral tongue were treated at the University of Colorado Denver. Of the 50 patients, 38 had newly diagnosed SCC of the oral tongue (13 with stage I-II and 25 with stage III-IV disease), and 12 presented with locally recurrent SCC. Of the 50 patients, 49 were treated with initial surgery and 1 with definitive chemoradiotherapy. Adjuvant radiotherapy or chemoradiotherapy was administered to 42 patients after surgery. Of the 13 patients with newly diagnosed stage I-II disease, 7 did not receive adjuvant therapy. The actuarial locoregional control, freedom from distant relapse, and survival were determined using the Kaplan-Meier method, and comparisons were made using the log-rank test. RESULTS: The median follow-up was 29 months (range 4 to 95) for living patients. The 2-year locoregional control and freedom from distant relapse rate was 58% and 83%, respectively. Locoregional control was particularly low among patients with stage I-II disease, for whom the 2-year locoregional control rate was only 35%. The median survival time and 2-year survival rate for all patients was 42 months and 65%, respectively. The 2-year survival rate for patients with stage I-II oral tongue cancer was 77% compared with 52% for patients with stage III-IV disease (P = .04). CONCLUSIONS: Despite aggressive therapy, patients with SCC of the oral tongue have a low rate of local tumor control and survival, particularly among those with stage I-II disease. These patients should be considered for inclusion in clinical trials evaluating novel postoperative therapies.

Improved survival in patients with Stage III-IV Head and neck cancer treated with radiotherapy as primary local treatment modality.

PURPOSE: To evaluate the overall and cause-specific survival in patients with Stage III-IVb head and neck squamous cell carcinoma treated with radiotherapy (RT) as the primary local treatment modality. METHODS AND MATERIALS: The survival of patients with American Joint Committee on Cancer Stage III-IVb head and neck squamous cell carcinoma treated with primary RT was queried using the Surveillance, Epidemiology and End Results database. The effect of the year of treatment on overall and cause-specific survival was analyzed as a categorical and continuous variable. The patterns of care for these patients were also evaluated. RESULTS: Between 1988 and 2004, 6,759 patients were identified. Survival was significantly improved in patients treated more recently. When analyzed as a continuous variable, each year was associated with a 3% and 4.1% reduction in the relative risk of overall and cause-specific mortality, respectively (p < 0.0001). Patients treated after 1998 had a 7.6% and 6.1% absolute improvement in overall and cause-specific survival, respectively, compared with patients treated before 1998 (overall survival, hazard ratio, 0.81; cause-specific survival, hazard ratio, 0.77; p < 0.0001). This benefit in survival was limited to tumors of the oral cavity, oropharynx, and hypopharynx. The use of RT increased among patients treated more recently. This shift in patterns of care was most pronounced for tumors of the larynx and hypopharynx. CONCLUSIONS: The overall and cause-specific survival of patients with Stage III-IVb head and neck squamous cell carcinoma treated with primary RT has improved with time. The improvement is consistent with that observed in a large meta-analysis of randomized patients treated with concurrent chemoradiotherapy.

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.

A phase I dose-escalation study of fractionated stereotactic radiosurgery in combination with gefitinib in patients with recurrent malignant gliomas.

PURPOSE: To determine the maximum tolerated dose (MTD) of fractionated stereotactic radiosurgery (SRS) with gefitinib in patients with recurrent malignant gliomas. METHODS AND MATERIALS: A Phase I clinical trial was performed. Eligible patients had pathologically proved recurrent anaplastic astrocytoma or glioblastoma. Patients started gefitinib (250 mg/day) 7 days before SRS and continued for 1 year or until disease progression. SRS was delivered in three fractions over 3 days. The planning target volume (PTV) was the T1-weighted MRI postcontrast enhancing lesion+2 mm. The first cohort received an SRS dose of 18 Gy, and subsequent cohorts received higher doses up to the maximum dose of 36 Gy. Dose-limiting toxicity (DLT) was any Grade 3 toxicity. The MTD was exceeded if 2 of 6 patients in a cohort experienced DLT. RESULTS: Characteristics of the 15 patients enrolled were: 9 men, 6 women; median age, 47 years (range, 23-65 years); 11 glioblastoma, 4 AA; median prior RT dose, 60 Gy (range, 54-61.2 Gy); median interval since RT, 12 months (range, 3-57 months); median PTV, 41 cc (range, 12-151 cc). Median follow-up time was 7 months (range, 2-28 months). Median time on gefitinib was 5 months (range, 2-12 months). No patient experienced a DLT, and the SRS dose was escalated from 18 to 36 Gy. Grade 1-2 gefitinib-related dermatitis and diarrhea were common (10 and 7 patients, respectively). CONCLUSION: Fractionated SRS to a dose of 36 Gy in three fractions is well tolerated with gefitinib at daily dose of 250 mg. Further studies of SRS and novel molecular targeted agents are warranted in this challenging clinical setting.

Effect of radiation techniques in treatment of oropharynx cancer.

OBJECTIVES: To compare the toxicity and outcomes of three radiotherapy techniques-three-dimensional conformal (3D-RT), accelerated fractionation with concomitant boost (AFxCB), and intensity modulated radiotherapy (IMRT)-in the combined modality treatment of stage III-IV squamous cell carcinoma (SCC) of the oropharynx. STUDY DESIGN: Retrospective review. METHODS: Between 1998 and 2007, a total of 87 patients were treated; 23 were treated with 3D-RT, 32 with AFxCB, and 32 with IMRT. Systemic therapy consisted of platinum-based chemotherapy in 81 and anti-epidermal growth factor receptor (anti-EGFR)-targeted therapy in 6 cases. Median radiotherapy doses were 70Gy with 3D-RT, 72Gy with AFxCB, and 69.3Gy with IMRT. Locoregional control, survival outcomes, and feeding tube (PEG) dependence were compared using log-rank method. The incidence of acute mucositis and skin reaction, and grade > or = 2 xerostomia at 6, 12, and 18 months after radiotherapy was compared using Fisher's exact test. RESULTS: Median follow-up was 24 months (range 3 to 103 months) for living patients. Two-year overall survival (OS), disease-free survival (DFS), and locoregional control (LRC) were 77.3%, 69.5%, and 86.4%, respectively. There was a trend toward improvement in LRC in patients treated with IMRT. Acute grade > or = 3 skin and mucosal toxicity were significantly lower with IMRT compared to AFxCB (P < .001). Grade > or = 2 xerostomia was significantly reduced with IMRT compared to AFxCB and 3D-RT (P < .001). There was no difference in the actuarial rate of PEG dependence (P = .96). CONCLUSIONS: Compared to AFxCB and 3D-RT, IMRT confers an improvement in toxicity and appears to have similar efficacy in patients with SCC of the oropharynx.

A Phase II multi-institutional trial of chemoradiation using weekly docetaxel and erythropoietin for high-risk postoperative head and neck cancer patients.

PURPOSE: To determine efficacy and toxicities of postoperative concurrent chemoradiation using docetaxel in high-risk head and neck cancer. METHODS AND MATERIALS: High-risk patients were enrolled 2-8 weeks after surgery. Treatment included 60 Gy for 6 weeks with weekly docetaxel 25 mg/m(2) and erythropoietin alpha 40,000 U for hemoglobin < or =12 g/dL. Primary endpoints included locoregional control (LC), disease-free survival (DFS), and patterns of failure (POF). Secondary endpoints were toxicity and quality of life. RESULTS: Eighteen patients were enrolled (14 male, 4 female), aged 24-70 years (median, 55 years). Primary site included oropharynx = 7, oral cavity = 8, hypopharynx = 1, and larynx = 2. Pathologic American Joint Committee on Cancer Stage was III = 3 patients, IV = 15 patients. High-risk eligibility included > or =2 positive lymph nodes = 13, extracapsular extension = 10, positive margins = 8 (11 patients with two or more risk factors). Docetaxel was reduced to 20 mg/m(2)/week after 5 patients had prolonged Grade 3 or higher mucositis. Overall, number of doses delivered was 2 of 6 = 1, 3 of 6 = 2, 4 of 6 = 2, 5 of 6 = 4, 6 of 6 = 9 patients. With median follow-up of 30 months (range, 5-66), 10 (56%) patients are alive and have no evidence of disease (NED); POF: three local recurrences (two with distant) and 1 distant only. One-year survival was 76%, median PFS and DFS had not been reached. Three-year LC was 82%. No Grade 3 or higher late toxicities were observed, although a few cases of prolonged mucositis and taste loss (>3 months) were seen, particularly at 25 mg/m(2)/week. CONCLUSION: Postoperative radiation therapy with weekly docetaxel 20 or 25 mg/m(2)/week for high-risk postoperative head and neck cancer caused intolerable mucosal toxicity, prompting early study termination. Further studies should consider 15 mg/m(2). Actuarial 3-year LC is 82%, similar to cisplatin-based chemoradiation regimens. Distant metastasis remains an important issue requiring additional systemic interventions.

Current radiation therapy management issues in oral cavity cancer.

Oral cavity cancer presents a therapeutic challenge to the treating surgeons,radiation oncologists, and medical oncologists. In early-stage disease, surgery or radiation alone often achieves excellent local control. Patients who have risk factors for recurrence after surgery should undergo adjuvant radiotherapy or chemoradiotherapy. In locally advanced disease, recurrence rates and deaths caused by disease progression continue to be unacceptably high. During the past decade, multiple randomized studies have shown a benefit in the addition of chemotherapy to radiation in the definitive or postoperative setting. Also, hyperfractionated and concomitant boost radiotherapy has shown superior results when compared with conventional once-daily radiotherapy. The addition of chemotherapy to hyperfractionated or concomitant boost radiotherapy also seems to improve outcomes at the cost of increased toxicities. In addition to traditional therapeutic modalities, new targeted agents seem promising to improve outcomes and possibly allow use of decreased doses of chemotherapy or radiotherapy, thus decreasing the toxicity of treatment.Overall, the management of cancer of the oral cavity is evolving rapidly,and a multidisciplinary approach to the patient who has oral cavity cancer is important to ensure the highest quality of patient care.

Phase I study of vandetanib with radiation therapy with or without cisplatin in locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Vandetanib, added to cisplatin and radiation therapy (RT) overcomes chemoradiation therapy (CRT) and epidermal growth factor receptor (EGFR) inhibitor resistance in head and neck squamous cell carcinoma (HNSCC) lines and models. METHODS: Patients with previously untreated HNSCC received vandetanib daily for 14 days (starting dose 100 mg) and then vandetanib + RT (2.2 Gy/day, 5 days/week) for 6 weeks (regimen 1) or vandetanib + RT (2 Gy/day, 5 days/week) + cisplatin (30 mg/m(2) weekly) for 7 weeks (regimen 2). The primary objective was the maximum tolerated dose (MTD) of vandetanib with RT +/- cisplatin. RESULTS: Of 33 treated patients, 30 completed therapy (regimen 1, n = 12; regimen 2, n = 18). MTD in regimen 2 was 100 mg (3 dose limiting toxicities [DLTs] at 200 mg), whereas regimen 1 was stopped because of poor recruitment (1 DLT at 200 mg). Most common grade ≥3 adverse events (AEs) were dysphagia (30%), stomatitis (33%), and mucosal inflammation (27%). Five patients discontinued vandetanib because of AEs. CONCLUSION: Vandetanib with CRT was feasible.

Volumetric considerations in radiotherapy for pediatric parameningeal rhabdomyosarcomas.

PURPOSE: To assess the influence of radiation volume on outcome in pediatric parameningeal rhabdomyosarcomas (PM-RMSs). METHODS AND MATERIALS: Thirty patients ranging in age from 2 to 18 years (median 6) with PM-RMS were treated at the Hospital of the University of Pennsylvania and the Children's Hospital of Philadelphia between August 1988 and December 1999. The histologic subtypes included embryonal (n = 26), alveolar (n = 3), and undifferentiated (n = 1). Twenty-seven patients had Group III and three had Group IV disease. Twenty-seven patients underwent biopsy only and three subtotal resection. All patients were treated with multiple-agent chemotherapy and external beam radiotherapy. In 8 patients, all of whom had intracranial tumor extension, the tumor and whole brain were treated as the initial volume. In the remaining patients, most of those treated before 1992 were treated to the prechemotherapy (CMT) tumor volume for the entire treatment up to the total dose, which ranged from 45 to 59.4 Gy (median dose 57.9). In contrast, patients treated after 1992 generally received radiation initially to the pre-CMT volume (30.6-40 Gy; median dose 36) followed by a conedown to the post-CMT volume to a final dose of 41.4-55.2 Gy (median 50.4). RESULTS: With a median follow-up of 6.2 years (range 2.1-13.3), the actuarial 5-year overall survival, progression-free survival, and local control rate for the entire group was 82%, 76%, and 76%, respectively. Seven failures and five deaths have been documented. In univariate analysis, histologic type, tumor size, and age at diagnosis were found to be predictive of overall survival and local control. No statistically significant difference in overall survival or local control was seen between patients who received a conedown to the post-CMT volume (n = 13) and patients in whom the pre-CMT volume was included for the entire treatment (n = 9). CONCLUSION: Radiotherapy delivered to children with PM-RMS using a shrinking field technique with a post-CMT volume boost was effective and appears to give results comparable to those of patients in whom the pre-CMT volume was treated for the entire course. The use of such tailored treatment fields is likely to lead to fewer late effects and warrants further investigation.

Outcome after treatment of patients with mammographically occult, magnetic resonance imaging-detected breast cancer presenting with axillary lymphadenopathy.

Although magnetic resonance imaging (MRI) for patients with mammographically occult breast cancer with axillary lymphadenopathy has been accepted for staging, treatment outcome data in this patient group is lacking. In this study, 16 patients, median age of 45 years (range, 27-66 years), presented with malignant axillary lymphadenopathy, negative mammograms, negative breast physical examination, and abnormal breast MRI. All 16 patients were found to have >/= 1 suspicious lesions on breast MRI. Ten patients had a solitary enhancing lesion; 1 patient had 2 enhancing lesions; 3 patients had 3 enhancing lesions; 1 patient had a mass lesion and diffuse patchy enhancement in the breast; and 1 patient had regional enhancement but no discrete lesion on MRI. Six patients underwent breast-conservation surgery using MRI-guided wire localization and 10 patients had modified radical mastectomy. Fourteen patients received adjuvant chemotherapy and the remaining 2 patients received neoadjuvant chemotherapy. With a median follow-up of 5 years (range, 1.2-7.6 years), the 5-year actuarial local control was 100%, relapse-free survival was 74%, and overall survival was 87%. Three patients developed distant metastases. Two patients died from distant metastases, and 1 patient is alive with metastatic disease. One patient had a relapse in the contralateral axilla and was treated with paclitaxel and is disease free. Although the patient population is small, the outcome after treatment for this group of patients with a mammographically occult, MRI-detected breast cancer presenting with axillary adenopathy is similar to the expected outcome for patients with breast cancer with positive axillary lymph nodes.

Breast conservation treatment for patients presenting with axillary lymphadenopathy from presumed primary breast cancer: the role of breast magnetic resonance imaging for staging.

Three female patients presented with malignant axillary lymphadenopathy presumed to be from primary breast cancer. No evidence of primary cancer was found in the breast on either mammography or breast magnetic resonance imaging (MRI). All 3 patients underwent axillary lymph node dissection and systemic chemotherapy followed by radiation therapy to the breast and regional lymph nodes. Two patients remain relapse free with a follow-up of 3.7 years each. The third patient achieved locoregional control in the ipsilateral breast and regional lymph nodes but relapsed in the contralateral axilla. These 3 cases illustrate the potential for breast conservation treatment for patients presenting with axillary adenopathy from a presumed primary breast cancer but without either mammographic or breast MRI findings.

Emerging role of EGFR-targeted therapies and radiation in head and neck cancer.

The treatment of head and neck cancer has been at the forefront of novel therapeutic paradigms. The introduction of drugs that interact with selective biologic pathways in the cancer cell has generated considerable attention recently. A wide variety of new compounds that attempt to target growth-signaling pathways have been introduced into the clinic. A majority of studies in the clinic have focused on epidermal growth factor receptor (EGFR) antagonists, but future studies will likely build upon or complement this strategy with agents that target angiogenic or cell-cycle pathways. EGFR activation promotes a multitude of important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Since radiation therapy plays an integral role in managing head and neck squamous cell cancer (HNSCC), inhibiting the EGFR pathway might improve our efforts at cancer cure. The challenge now is to understand when the application of these EGFR inhibitors is relevant to an individual patient and how or when these drugs should be combined with radiation or chemotherapy. Are there molecular markers available to determine who will respond to EGFR inhibitors and who should be treated with alternative approaches? What are the mechanisms behind intrinsic or acquired resistance to targeted agents, and how do we prevent this problem? We need to formulate integrated laboratory/clinical research programs that address these important issues.

Hypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy may alter the patterns of failure in patients with glioblastoma multiforme.

INTRODUCTION: The objective of this study was to report the patterns of failure in patients with glioblastoma multiforme (GBM) treated on a phase II trial of hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concurrent and adjuvant temozolomide (TMZ). METHODS: Patients with newly diagnosed GBM post-resection received postoperative hypo-IMRT to 60 Gy in 10 fractions. TMZ was given concurrently at 75 mg/m(2) /day for 28 consecutive days and adjuvantly at 150-200 mg/m(2) /day for 5 days every 28 days. Radiographic failure was defined as any new T1-enhancing lesion or biopsy-confirmed progressive enhancement at the primary site. MRIs obtained at the time of failure were fused to original hypo-IMRT plans. Central, in-field, marginal and distant failure were defined as ≥95%, 80% to 95%, any to 80% and 0% of the volume of a recurrence receiving 60 Gy, respectively. RESULTS: Twenty-four patients were treated on the trial. Median follow-up was 14.8 months (range 2.7-34.2). Seventeen of 24 patients experienced radiographic failure: one central, five in-field, two marginal, eight distant and one both in-field and distant. Two of the eight distant failures presented with leptomeningeal disease. Two other patients died without evidence of radiographic recurrence. Five of 24 patients demonstrated asymptomatic, gradually progressive in-field T1 enhancement, suggestive of post-treatment changes, without clear evidence of failure; three of these patients received a biopsy/second resection, with 100% radiation necrosis found. The median overall survival of this group was 33.0 months. CONCLUSION: A 60-Gy hypo-IMRT treatment delivered in 6-Gy fractions with TMZ altered the patterns of failure in GBM, with more distant failures.

MRI patterns of T1 enhancing radiation necrosis versus tumour recurrence in high-grade gliomas.

INTRODUCTION: Despite the emergence of new imaging technologies, the differentiation of treatment-related changes from recurrent tumour in patients with high-grade gliomas remains a difficult challenge. We evaluated whether specific MRI (magnetic resonance imaging) T1 post-contrast enhancement patterns can help to distinguish between radiation necrosis and tumour recurrence. METHODS: This study was approved by local institutional review board. Fifty-one patients with World Health Organization grade III-IV glioma underwent reoperation after prior chemoradiation. The percentage of radiation necrosis versus recurrent tumour in reoperation specimens was estimated by an experienced neuropathologist. Enhancement patterns on T1 post-contrast sequences from the MRIs obtained prior to reoperation were evaluated according to pathology. RESULTS: T1 contrast enhancement patterns correlating with recurrent tumour included focal solid nodules and solid uniform enhancement with distinct margins. Eighty-five per cent (17/20) of patients with ≥70% recurrent tumour at reoperation demonstrated one of these patterns on preoperative MRI. Enhancement patterns correlating with radiation necrosis included a hazy mesh-like diffuse enhancement and rim enhancement with feathery indistinct margins. Ninety-four per cent (17/18) of patients with ≥70% radiation necrosis demonstrated one of these two patterns. Thirteen cases had more mixed pathology (>30% of tumour/necrosis) and demonstrated patterns associated with recurrence and/or necrosis. Compared to MR spectroscopy performed in 10 patients, enhancement patterns on MRI were just as accurate in predicting pathologic diagnosis. CONCLUSION: Identifying distinct patterns of contrast enhancement on MRI may help to differentiate between radiation necrosis and tumour recurrence in high-grade gliomas.

Sparing the larynx and esophageal inlet expedites feeding tube removal in patients with stage III-IV oropharyngeal squamous cell carcinoma treated with intensity-modulated radiotherapy.

OBJECTIVES/HYPOTHESIS: To evaluate the effect of larynx and esophageal inlet sparing on dysphagia recovery after intensity-modulated radiotherapy (IMRT) for stage III-IV oropharyngeal squamous cell carcinoma. STUDY DESIGN: Retrospective study. METHODS: Of 88 patients treated with IMRT, 38 were planned with a larynx + esophageal inlet mean dose <50 Gy constraint, 27 with a larynx alone mean dose constraint of <50 Gy, and 23 without a larynx/esophagus constraint. All had a percutaneous endoscopic gastrostomy (PEG) tube placed before IMRT, which was removed when the patient could swallow and maintain weight. All IMRT plans were retrieved, and the larynx; esophageal inlet; and superior, middle, and inferior constrictors were contoured. Dosimetric data were correlated with PEG tube dependence duration. RESULTS: The PEG tube was removed within 3, 6, 9, and 12 months after IMRT in 24%, 61%, 71%, and 83% of patients, respectively. Median times to PEG tube removal were 3.7 and 8.6 months (P = .0029) in patients planned with or without a larynx/larynx + esophageal inlet dose constraint. A mean dose to the larynx + esophageal inlet of ≤60 Gy reduced the median PEG tube duration from 10.8 to 6.1 months (P = .02), compared to >60 Gy. Mean pharyngeal constrictor doses in patients receiving a mean dose to the larynx + esophageal inlet of ≤50 Gy versus >50 Gy were: 60 Gy and 69 Gy, 55 Gy and 67 Gy, and 47 Gy and 57 Gy, for the superior, middle, and inferior constrictors, respectively (P < .0001). CONCLUSIONS: A dose constraint on the larynx and esophageal inlet during IMRT planning reduces dose to pharyngeal constrictors and expedites PEG tube removal.