Comparison of manual and automatic segmentation methods for brain structures in the presence of space-occupying lesions: a multi-expert study.

The purpose of this work was to characterize expert variation in segmentation of intracranial structures pertinent to radiation therapy, and to assess a registration-driven atlas-based segmentation algorithm in that context. Eight experts were recruited to segment the brainstem, optic chiasm, optic nerves, and eyes, of 20 patients who underwent therapy for large space-occupying tumors. Performance variability was assessed through three geometric measures: volume, Dice similarity coefficient, and Euclidean distance. In addition, two simulated ground truth segmentations were calculated via the simultaneous truth and performance level estimation algorithm and a novel application of probability maps. The experts and automatic system were found to generate structures of similar volume, though the experts exhibited higher variation with respect to tubular structures. No difference was found between the mean Dice similarity coefficient (DSC) of the automatic and expert delineations as a group at a 5% significance level over all cases and organs. The larger structures of the brainstem and eyes exhibited mean DSC of approximately 0.8-0.9, whereas the tubular chiasm and nerves were lower, approximately 0.4-0.5. Similarly low DSCs have been reported previously without the context of several experts and patient volumes. This study, however, provides evidence that experts are similarly challenged. The average maximum distances (maximum inside, maximum outside) from a simulated ground truth ranged from (-4.3, +5.4) mm for the automatic system to (-3.9, +7.5) mm for the experts considered as a group. Over all the structures in a rank of true positive rates at a 2 mm threshold from the simulated ground truth, the automatic system ranked second of the nine raters. This work underscores the need for large scale studies utilizing statistically robust numbers of patients and experts in evaluating quality of automatic algorithms.

Nuclear factor-kappa B pathway and response in a phase II trial of bortezomib and docetaxel in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Our previous study has shown that nuclear factor-kappa B (NF-kappaB)-signaling pathway was associated with a higher rate of recurrence in head and neck squamous cell carcinoma (HNSCC). The combination of bortezomib, an NF-kappaB inhibitor by inhibition of proteasomes, plus docetaxel was assessed for efficacy and toxicity. MATERIALS AND METHODS: Patients with recurrent and/or metastatic HNSCC were enrolled on a phase II bortezomib/docetaxel trial (bortezomib 1.6 mg/m(2) and docetaxel 40 mg/m(2) on days 1 and 8 of a 21-day cycle). Response was assessed using RECIST. Tissue specimens were evaluated for the presence of human papillomavirus (HPV) and expression of NF-kappaB-associated genes. RESULTS: Twenty-one of 25 enrolled patients were assessable for response; one partial response (PR, 5%), 10 stable disease (SD, 48%) and 10 progressive disease (PD, 48%). Patients with PR/SD had significantly longer survival compared with patients with PD and the regimen was well tolerated. Only one of 20 tumors was positive for HPV. Patients with PD had higher expression of NF-kappaB and epidermal growth factor receptor-associated genes in their tumors by gene expression analysis. CONCLUSION: Further understanding of treatment resistance and interactions between bortezomib and docetaxel may provide novel approaches in managing HNSCC.

A phase I-B trial of the radiosensitizer: etanidazole (SR-2508) with radiosurgery for the treatment of recurrent previously irradiated primary brain tumors or brain metastases (RTOG Study 95-02).

RTOG 95-02 assessed patient tolerance to hypoxic cell radiosensitizer, etanidazole (SR-2508), combined with radiosurgery. Patients had primary or metastatic brain tumors and previously localized or whole brain irradiation. The toxicity is reported in three groups of patients according to the tumor size. Etanidazole doses of 12g/m2 combined with radiosurgery were well tolerated.

Low-dose stereotactic radiosurgery is inadequate for medically intractable mesial temporal lobe epilepsy: a case report.

The successful surgical treatment of medically refractory epilepsy is based on one of three different principles: (1) elimination of the epileptic focus, (2) interruption of the pathways of neural propagation, and (3) increasing the seizure threshold through cerebral lesions or electrical stimulation. Temporal lobe epilepsy, being the most common focal epilepsy, may ultimately require temporal lobectomy. This is a case report of a 36-year-old male with drug-resistant right mesial temporal lobe epilepsy who failed to obtain seizure control after stereotactic radiosurgery to the seizure focus. Complex-partial seizures occurred 6-7 times monthly, and consisted of a loss of awareness followed by involuntary movements of the right arm. EEG/CC TV monitoring indicated a right mesial temporal lobe focus, which was corroborated by decreased uptake in the right temporal lobe by FDG-PET and by MRI findings of right hippocampal sclerosis. Stereotactic radiosurgery was performed with a 4MV linac, utilizing three isocenters with collimator sizes of 10, 10, and 7 mm respectively. A dose of 1500 cGy (max dose 2535 cGy) was delivered in a single fraction to the patient's right amygdala and hippocampus. There were no acute complications. Following radiosurgery the patient's seizures were improved in both frequency and intensity for approximately 3 months. Antiepileptic medications were continued. Thereafter, seizures increased in both frequency and intensity, occurring 10-20 times monthly. At 1 year post radiosurgery, standard right temporal lobectomy including amygdalohippocampectomy was performed with subsequent resolution of complex-partial seizures. Histopathology of the resected temporal lobe revealed hippocampal cell loss and fibrillary astrocytosis, consistent with hippocampal sclerosis. No radiation-induced histopathologic changes were seen. We conclude that low-dose radiosurgery doses temporarily changed the intensity and character of seizure activity, but actually increased seizure activity long-term. If radiosurgery is to be an effective alternative to temporal lobectomy for medically intractable temporal lobe epilepsy, higher radiosurgery doses will be required. The toxicity and efficacy of higher-dose radiosurgery is currently under investigation.

Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature.

Radiation can be used to guide drugs to specific sites such as neoplasms or aberrant blood vessels. When blood vessels are treated with ionizing radiation, they respond by expressing a number of cell adhesion molecules and receptors that participate in homeostasis. Examples of radiation-induced molecules in blood vessels include ICAM-1, E-selectin, P-selectin and the beta(3) integrin. We have observed that the endothelium and blood components respond to oxidative stress in a similar, if not identical manner in all tumor models. Although we have identified several other radiation-induced molecules within tumor blood vessels, the beta(3) target for drug delivery achieves the greatest site-specific peptide binding within irradiated tumor blood vessels. We have focused on peptides and antibodies that bind to integrin beta(3). beta(3)-binding proteins have been conjugated to fluorochromes and radionuclides to study the site specificity and microscopic distribution. We have found immunofluorescent and immunohistochemical staining of beta(3) within the lumen of blood vessels immediately following irradiation. To determine whether it is feasible to guide drug delivery to irradiated tumors, we studied ligands to alpha(2b)beta(3) (fibrinogen). Peptides within fibrinogen that bind to alpha(2b)beta(3) includes the dodecapeptide, HHLGGAKQAGDV and the RGD peptide. We utilized 131I conjugation to these ligands to study the biodistribution in tumor bearing mice. Our clinical trial consists of the RGD peptidomimetic, biapcitide, labeled with 99mTc. This study shows that it is feasible to guide drugs to human neoplasms by use of radiation-guided peptides. These studies have shown that peptides that bind to these integrins bind to tumors following exposure to ionizing radiation.

Patterns of practice survey for nonsmall cell lung carcinoma in the U.S.

BACKGROUND: Nonsmall cell lung carcinoma comprises approximately 75% of all lung carcinoma cases in the U.S. Newly evolving strategies have created considerable controversy regarding the optimal treatment for patients diagnosed with this disease. METHODS: A 17-item survey was designed to collect demographic data and information regarding practice patterns for nonsmall cell lung carcinoma, including patient assessment, treatment approaches, and roles of chemotherapy and radiotherapy. Surveys were mailed in the summer of 1997 to approximately 9200 oncologists of all types throughout the U.S. Practice settings included private office, private hospital, academic, university-affiliated office, government, and Veterans Administration institutions. RESULTS: Approximately 10% of the oncologists responded (n = 979), including 499 medical oncologists (51%), 464 radiation oncologists (47%), and 16 others (2%). For the adjuvant treatment of surgically resected N1-2 disease, combined modality treatment was preferred over radiation therapy alone by medical oncologists (48% vs. 16%; P<0.001) and radiation therapy alone was preferred over combined modality treatment by radiation oncologists (55% vs. 38%; P<0.001). The combination of paclitaxel and carboplatin was the preferred first-line regimen for all stages of nonsmall cell lung carcinoma by the majority of medical oncologists (55%), whereas the majority of radiation oncologists (58%) chose the combination of etoposide and platinum. With regard to the optimal combined modality approach, respondents were divided evenly between concurrent chemoradiotherapy (34%) and sequential chemoradiotherapy (31%). Overall, respondents reported basing treatment decisions largely on published literature (55%) compared with personal experience (19%), seminars and colleagues (16%), and clinical trial availability (10%) (P<0.001). CONCLUSIONS: This survey confirms many differences in practice patterns among medical oncologists and radiation oncologists in the treatment of patients with nonsmall cell lung carcinoma and suggests the need for the multidisciplinary management of this entity. In addition, the current study demonstrates that reliance on the medical literature as a basis for treatment steadily declines the longer the physician has been in practice.

Drug-radiation interactions in tumor blood vessels.

Obliteration of the tumor vasculature is an effective means of achieving tumor regression. Antiangiogenic agents have begun to enter cancer clinical trials. Ionizing radiation activates the inflammatory cascade and increases the procoagulative state within blood vessels of both tumors and normal tissues. These responses are mediated through oxidative injury to the endothelium, leading to induction of cell-adhesion molecules and exocytosis of stored proteins from the endothelial cytoplasm. Agents that activate homeostatic responses in the endothelium can enhance thrombosis and vasculitis of irradiated tumor blood vessels. Proinflammatory and prothrombotic biological response modifiers given concurrently with ionizing radiation are known to induce vascular obliteration and necrosis of tumors. Other mechanisms of interaction between antiangiogenic agents and ionizing radiation include the direct cytotoxic effects of these agents. Interactions between drugs and radiation therapy might therefore occur at the level of the vascular endothelium. The importance of this paradigm is that the endothelium might not develop resistance to drugs or radiation because of lessened potential for mutagenesis and clonogenesis. The future design of clinical trials must consider the effects of radiation therapy on the vascular endothelium.

Combined-modality therapy for locoregionally advanced head and neck cancer.

Traditionally, treatment for locally advanced resectable head and neck cancer has been surgical resection followed by postoperative radiation. In unresectable patients, primary radiation has been the mainstay of treatment. In an attempt to improve local control and survival, chemotherapy has been investigated as an adjunct to locoregional treatment. Induction or adjuvant chemotherapy in combination with primary surgical resection has failed to demonstrate an improvement in either local control or survival. Induction chemotherapy followed by radiation therapy is an acceptable alternative to surgical resection for organ preservation. A randomized trial in patients with advanced oropharyngeal carcinoma and another in advanced nasopharyngeal carcinoma have shown an improvement in survival with the use of concomitant chemotherapy and radiation compared to radiation alone. Other prospective randomized trials as well as three meta-analyses also demonstrate improved survival with the addition of concomitant chemotherapy for locally advanced disease. Newer chemotherapeutic agents are currently under investigation, particularly those with radiosensitizing properties. Chemotherapy as part of primary therapy, however, should be used judiciously, and should be based on an assessment of the potential risks and benefits to each patient.

National survey on prophylactic cranial irradiation: differences in practice patterns between medical and radiation oncologists.

PURPOSE: Prophylactic cranial irradiation (PCI) in the treatment of small cell lung cancer (SCLC) patients remains controversial in the oncology community because of its potential for long-term toxicity and unproven survival benefit in randomized trials. A national survey of 9176 oncologists was conducted to characterize the use of PCI with regard to physician demographics, patient characteristics, and oncologists' beliefs. METHODS: Data was collected via a questionnaire letter survey. Biographical data, treatment patterns, and clinical impressions were analyzed by the generalized linear model and generalized estimating equations method. RESULTS: There were 1231 responders overall (13.4% of those surveyed), including 628 (51%) radiation oncologists (RO), 587 (48%) medical oncologists (MO), 8 (0.6%) surgical oncologists, and 8 (0.6%) from other oncology subspecialties. Of respondents, 74% overall recommend PCI in limited-stage patients, including 65% of MO and 82% RO (p = 0.001). Of responders who recommend PCI in limited-stage patients, 67% do so only after complete response to initial therapy. Only 30% of respondents recommend PCI for extensive-stage SCLC patients (p = 0.001), and 94% of these recommend PCI only when those patients have a complete response after initial therapy. Interestingly, 38% of responding MO feel that PCI improves survival of limited-stage patients, but only 11% believe PCI improves quality of life. Of the RO, 48% believe PCI improves survival in limited-stage SCLC, and 36% feel PCI improves quality of life (p < 0.05 and p < 0.01, respectively). MO responders believe PCI causes late neurological sequelae more often than do RO responders (95% vs. 84%, p < 0.05), with impaired memory (37%), chronic fatigue (19%), and loss of motivation (13%) as most commonly seen side effects. Only 1.5% overall, however, routinely obtain neuropsychiatric testing in PCI patients, and 42% overall never obtain them. CONCLUSION: Results confirm that oncologic subspecialists have statistically significant differences in opinion regarding the use of PCI. However, these differences may not translate into large differences in clinical practice. Most oncologists continue to recommend PCI in limited-stage SCLC patients, despite many believing PCI may not provide a survival advantage nor improve quality of life.

Long-term survival with whole abdominopelvic irradiation in platinum-refractory persistent or recurrent ovarian cancer.

The purpose of this study is to retrospectively evaluate the efficacy and toxicity of whole abdominopelvic irradiation (WAI) in patients with persistent or recurrent epithelial ovarian carcinoma who failed chemotherapy. Between 1970 and 1995, 41 women with persistent or recurrent ovarian carcinoma after initial treatment with surgical debulking and chemotherapy (4 to 18 cycles; median, 8) were treated with WAI. Thirty-one patients had received platinum-based regimens, and 22 of these had failed within 6 months after completion of chemotherapy ("platinum-refractory"). Prior to WAI, 11 (27%) patients had microscopic residual disease, 21 (51%) had gross residual disease up to 1.5 cm, and 9 (22%) had residual tumors greater than 1.5 cm in maximal diameter. Median doses of 28 Gy to the abdomen and 48 Gy to the pelvis were delivered using open-field techniques and liver and kidney shielding. With follow-up of 1 month to 16.5 years (median potential follow-up, 1.4 years), the 5-year actuarial disease-specific survival was 47% in all 41 patients, and 50% in the 22 platinum-refractory patients. Both residual tumor size at WAI (P < 10(-4)) and initial stage (P = 0.003) were of prognostic value. Five-year disease-specific survival of all patients with residual tumors less than 1.5 cm was 53%; 0% for patients with tumors greater than 1.5 cm. Five-year disease-specific survivals by initial stage were: stage I and II, 75%; stage III, 40%; and stage IV, 15%. Stage I, II, or III patients with residual disease up to 1.5 cm before WAI had a 10-year actuarial disease-specific survival of 40%. Twelve patients (29%) failed to complete the planned course of WAI due to acute toxicity (most often due to prolonged thrombocytopenia). Late toxicity (requiring surgery) included bowel obstruction in two patients and fistula in one patient. Whole abdominopelvic irradiation should be considered in selected patients who fail initial chemotherapy, especially in patients who can or have been debulked to small amounts of residual disease. With acceptable toxicity, WAI results appear to be as good as or better than second-line chemotherapy, particularly in platinum-refractory patients.

Radiosurgery for skull base malignancies and nasopharyngeal carcinoma.

PURPOSE: Patients with skull base lesions present a challenging management problem because of intractable symptoms and limited therapeutic options. In 1989 we began treating selected patients with skull base lesions using linac stereotactic radiosurgery. In this study the efficacy and toxicity of this therapeutic modality is investigated. METHODS AND MATERIALS: Forty-seven patients with 59 malignant skull base lesions were treated with linac radiosurgery between 1989 and 1995. Eleven patients were treated for primary nasopharyngeal carcinoma using radiosurgery as a boost (7 Gy-16 Gy, median: 12 Gy) to the nasopharynx after a course of fractionated radiotherapy (64.8-70 Gy) without chemotherapy. Another 37 patients were treated for 48 skull base metastases or local recurrences from primary head and neck cancers. Eight of these patients had 12 locally recurrent nasopharyngeal carcinoma lesions occuring 6-96 months after standard radiotherapy, including one patient with nasopharyngeal carcinoma who developed a regional relapse after radiotherapy with a stereotactic boost. Lesion volumes by CT or MRI ranged from 0 to 51 cc (median: 8 cc). Radiation doses of 7.0 Gy-35.0 Gy (median: 20.0 Gy) were delivered to recurrent lesions, usually as a single fraction. RESULTS: All 11 patients who received radiosurgery as a nasopharyngeal boost after standard fractionated radiotherapy remain locally controlled (follow-up: 2-34 months, median: 18). However, one patient required a second radiosurgical treatment for regional relapse outside the initial radiosurgery volume. Thirty-three of 48 (69%) recurrent/metastatic lesions have been locally controlled, including 7 of 12 locally recurrent nasopharyngeal lesions. Follow-up for all patients with recurrent lesions ranged from 1 to 60 months (median: 9 months). Local control did not correlate with lesion size (p = 0.80), histology (p = 0.78), or radiosurgical dose (p = 0.44). Major complications developed after 5 of 59 treatments (8.4%), including three cranial nerve palsies, one CSF leak, and one trismus. Complications were not correlated with radiosurgical volume (p = 0.20), prior skull base irradiation (p = 0.90), or radiosurgery dose > 20 Gy (p = 0.49). CONCLUSION: Stereotactic radiosurgery is a reasonable treatment modality for patients with skull base malignancies, including patients with primary and recurrent nasopharyngeal carcinoma. The dose distribution obtained with stereotactic radiosurgery provides better homogeneity than an intracavitary implant when used as a boost for nasopharyngeal lesions, especially lesions which involve areas distant to the nasopharyngeal mucosa.