The rates of second lung cancers and the survival of surgically-resected second primary lung cancers in patients undergoing resection of an initial primary lung cancer.

BACKGROUND: The Lung Cancer Screening Trial demonstrated improved overall survival (OS) and lung cancer specific survival (LCSS), likely due to finding early-stage NSCLC. The purpose of our investigation is to evaluate whether long-term surveillance strategies (4+ years after surgical resection of the initial lung cancer(1LC)) would be beneficial in NSCLC patients by assessing the rates of second lung cancers(2LC) and the OS/LCSS in patients undergoing definitive surgery in 1LC as compared to 2LC (>48 months after 1LC) populations. METHODS: SEER13/18 database was reviewed for patients during 1998-2013. Log-rank tests were used to determine the OS/LCSS differences between the 1LC and 2LC in the entire surgical group(EG) and in those having an early-stage resectable tumors (ESR, tumors <4 cm, node negative). Joinpoint analysis was used to determine rates of second cancers 4-10 year after 1LC using SEER-9 during years 1985-2014. RESULTS: The rate of 2LCs was significantly less than all other second cancers until 2001 when the incidence of 2LCs increased sharply and became significantly greater than all other second cancers in females starting in year 2005 and in men starting in year 2010. OS/LCSS, adjusted for propensity score by using inverse probability weighting, demonstrated similar OS, but worse LCSS for 2LCs in the EG, but similar OS/LCSSs in the ESR group. CONCLUSION: Because the rate of 2LCs are increasing and because the OS/LCSS of the 1LC and 2LC are similar in early-stage lesions, we feel that continued surveillance of patients in order to find early-stage disease may be beneficial.

CT versus MR Imaging in Estimating Cochlear Radiation Dose during Gamma Knife Surgery for Vestibular Schwannomas.

BACKGROUND AND PURPOSE: Leksell stereotactic radiosurgery is an effective option for patients with vestibular schwannomas. Some centers use a combination of stereotactic CT fused with stereotactic MR imaging to achieve an optimal target definition as well as minimize the radiation dose delivered to adjacent structures that correlate with hearing outcomes. The present prospective study was designed to determine whether there is cochlear dose variability between MR imaging and CT. MATERIALS AND METHODS: Fifty consecutive patients underwent stereotactic radiosurgery for vestibular schwannomas. Dose-planning was performed using high-definition fused stereotactic MR imaging and stereotactic CT images. The 3D cochlear volume was determined by delineating the cochlea on both CT and T2-weighted MR imaging. The mean radiation dose, maximum dose, and 3- and 4.20-Gy cochlear volumes were identified using standard Leksell Gamma Knife software. RESULTS: The median mean radiation dose delivered to the cochlea was 3.50 Gy (range, 1.20-6.80 Gy) on CT and 3.40 Gy (range, 1-6.70 Gy) on MR imaging (concordance correlation coefficient = 0.86, r 2 = 0.9, P ≤ .001). The median maximum dose delivered to the cochlea was 6.7 Gy on CT and 6.6 Gy on MR imaging (concordance correlation coefficient = 0.89, r 2 = 0.90, P ≤ .001). Dose-volume histograms generated from CT and MR imaging demonstrated a strong level of correlation in estimating the 3- and 4.20-Gy volumes (concordance correlation coefficient = 0.81, r 2 = 0.82, P ≤ .001 and concordance correlation coefficient = 0.87, r 2 = 0.89, P ≤ .001). CONCLUSIONS: Both MR imaging and CT provide similar cochlear dose parameters. Despite the reported superiority of CT in identifying bony structures, high-definition MR imaging alone is sufficient to identify the radiation doses delivered to the cochlea.

Characterization of pulmonary function in Duchenne Muscular Dystrophy.

Decline in pulmonary function in Duchenne Muscular Dystrophy (DMD) contributes to significant morbidity and reduced longevity. Spirometry is a widely used and fairly easily performed technique to assess lung function, and in particular lung volume; however, the acceptability criteria from the American Thoracic Society (ATS) may be overly restrictive and inappropriate for patients with neuromuscular disease. We examined prospective spirometry data (Forced Vital Capacity [FVC] and peak expiratory flow [PEF]) from 60 DMD patients enrolled in a natural history cohort study (median age 10.3 years, range 5-24 years). Expiratory flow-volume curves were examined by a pulmonologist and the data were evaluated for acceptability using ATS criteria modified based on the capabilities of patients with neuromuscular disease. Data were then analyzed for change with age, ambulation status, and glucocorticoid use. At least one acceptable study was obtained in 44 subjects (73%), and 81 of the 131 studies (62%) were acceptable. The FVC and PEF showed similar relative changes in absolute values with increasing age, i.e., an increase through 10 years, relative stabilization from 10-18 years, and then a decrease at an older age. The percent predicted, FVC and PEF showed a near linear decline of approximately 5% points/year from ages 5 to 24. Surprisingly, no difference was observed in FVC or PEF by ambulation or steroid treatment. Acceptable spirometry can be performed on DMD patients over a broad range of ages. Using modified ATS criteria, curated spirometry data, excluding technically unacceptable data, may provide a more reliable means of determining change in lung function over time.

Confirmation of the role of diabetes in the local recurrence of surgically resected non-small cell lung cancer.

PURPOSE: We recently demonstrated that diabetes mellitus was an independent risk factor for local recurrence (LR) for patients undergoing resection of non-small cell lung cancer (NSCLC). This investigation was performed to confirm or refute this finding in a different patient cohort. MATERIALS AND METHODS: Patients were eligible if they did not have a second primary cancer within 5 years of the original diagnosis, had at least 3-month follow-up, and did not receive radiotherapy. There were 373 and 168 patients in the original (P1) and confirmatory (P2) cohorts, respectively, with 66 and 30 patients with diabetes. RESULTS: The median follow-up was 33 months (range, 3-98 months). Diabetes was an independent risk factor for LR in a Cox model in both the P2 (p=0.05, hazard ratio [HR] 2.15) and P1 (p=0.008, HR 1.90) cohorts, separately from BMI, glucose control, and the presence of the metabolic syndrome. The rates of LR in the patients with diabetes after combining the cohorts at 2, 3, and 5 years were 23%, 33%, and 56%, respectively; these rates were 15%, 19%, and 26% in non-diabetics. In multivariate Cox regression and competing risk analysis of the combined cohorts, the HRs for LR in patients with diabetes exceeded those of more established risk factors for LR including a 1-cm increase in tumor size and lymphovascular invasion. CONCLUSIONS: Diabetes was confirmed to be an independent predictor of the risk of LR following resection of NSCLC.

Clinical and dosimetric factors associated with a prolonged feeding tube requirement in patients treated with chemoradiotherapy (CRT) for head and neck cancers.

BACKGROUND: Patients treated with chemoradiotherapy (CRT) for head and neck cancers often require feeding tubes (FTs) due to toxicity. We sought to identify factors associated with a prolonged FT requirement. PATIENTS AND METHODS: We retrospectively reviewed 80 patients treated with CRT for head and neck cancers. The pharyngeal constrictors (PCs), supraglottic larynx (SGL), and glottic larynx (GL) were contoured and the mean radiation doses and the volumes of each receiving >40, 50, 60, and 70 Gy (V40, V50, V60, and V70) were determined. RESULTS: A total of 33 of 80 patients required a FT either before or during the course of CRT. Fifteen patients required the FT for > or = 6 months. On univariate analysis, significant factors associated with a prolonged FT requirement were mean PC dose, PC-V60, PC-V70, SGL dose, SGL-V70, and advanced T3-T4 disease. Multivariate analyses found both PC-V70 and T3-T4 disease as significant factors .The proportions of patients requiring a FT > or = 6 months were 8% and 28% for treatment plans with PC-V70 <30% and > or = 30%, respectively. CONCLUSIONS: Increased radiation dose to the PCs is associated with a higher risk of a prolonged FT need. Dose sparing of the PC muscles may reduce this risk.

Gamma knife radiosurgery for multiple sclerosis-related trigeminal neuralgia.

BACKGROUND: Surgical options for multiple sclerosis (MS) related to trigeminal neuralgia (TN), a severe and disabling pain disorder, include percutaneous rhizotomy, stereotactic radiosurgery, or microsurgical nerve section. Our goal was to evaluate clinical outcomes after gamma knife radiosurgery (GKRS) in patients with MS with TN. METHODS: We evaluated clinical outcomes in 37 patients with TN managed over a 12-year period. The maximum TN target dose varied between 70 and 90 Gy. Seventy-eight percent of patients had failed prior surgery. In 9, GKRS was the first procedure. Median follow-up was 56.7 months (range, 6-174). Pain relief was assessed in each patient by physicians who did not participate in the surgery. RESULTS: Eventual complete pain relief (BNI grade I) after GKRS and reasonable pain control (BNI grade I-IIIb) after GKRS were noted in 23 patients (62.1%) and 36 patients (97.3%) at some point in their course. Reasonable pain control (BNI grade I-IIIb) after GKRS was maintained in 82.6%, 73.9%, and 54.0% of patients after 1, 3, and 5 years. Fourteen patients (37.8%) underwent a second or a subsequent procedure for residual or recurrent pain. Eight patients underwent a second GKRS, 5 underwent percutaneous glycerol rhizotomy, and 1 underwent balloon microcompression. The complication rate after GKRS was 5.4% (new onset of nondisabling paresthesias). No patient developed dysesthesias. CONCLUSIONS: Gamma knife radiosurgery is the most minimally invasive surgical technique for multiple sclerosis-related trigeminal neuralgia and has low morbidity. For this reason, gamma knife radiosurgery proved to be a satisfactory management strategy for multiple sclerosis-related trigeminal neuralgia.

Principles and practice of gamma knife radiosurgery: a review.

OBJECTIVES: To determine the physics, biology, outcomes and risks of gamma knife radiosurgery (GKRS) in treating brain tumours, arteriovenous malformations (AVMs), pain and movement disorders. DATA SOURCES: A retrospective MEDLINE search was used to find all gamma knife radiosurgery studies published from 1967 to 12th March 2005 and strict inclusion criteria were applied. STUDY SELECTION: Limited to the review articles in the human study with the key word of gamma knife radiosurgery. DATA EXTRACTION: In each subject, both authors reviewed related articles separately. DATA SYNTHESIS: Adding up data and compare the results. CONCLUSIONS: The GKRS represents one of the most advanced means available to treat brain tumours, arteriovenous malformations (AVMs), pain and movement disorders safely and effectively. At present, the long-term results after GKRS procedures remain to be documented. The physics, biology, current indications and expected outcomes after GKRS are discussed.

Sensitivity to radiation-induced apoptosis and neuron loss declines rapidly in the postnatal mouse neocortex.

Therapeutic brain irradiation can cause progressive decline in cognitive function, particularly in children, but the reason for this effect is unclear. The study explored whether age-related differences in apoptotic sensitivity might contribute to the increased vulnerability of the young brain to radiation. Postnatal day 1 (P1) to P30 mice were treated with 0-16 Gy whole-body X-irradiation. Apoptotic cells were identified and quantified up to 48 h later using the TdT-UTP nick end-labelling method (TUNEL) and immunohistochemistry for activated caspase-3. The number of neuron-specific nuclear protein (NeuN)-positive and -negative cells were also counted to measure neuronal and non-neuronal cell loss. Significantly greater TUNEL labelling occurred in the cortex of irradiated P1 animals relative to the other age groups, but there was no difference among the P7, P14 and P30 groups. Irradiation decreased the %NeuN-positive cells in the mice irradiated on P1, whereas in P14 animals, irradiation led to an increase in the %NeuN-positive cells. These data demonstrate that neocortical neurons of very young mice are more susceptible to radiation-induced apoptosis. However, this sensitivity decreases rapidly after birth. By P14, acute cell loss due to radiation occurs primarily in non-neuronal populations.

Fractionation of radiation treatment in acoustics. Rationale and evidence in comparison to radiosurgery.

Stereotactic fractionated radiotherapy has been proposed as a strategy to improve upon the results of single-fraction radiosurgery. The rationale for the strategy is that fractionation will allow complciations to be reduced while maintaining the same degree of long-term tumor control. This paper reviews the radiobiological arguements for fractionating radiation treatment of acoustic neuromas and examines claims for improvement in outcome.

Acoustic neuroma radiosurgery. Origins, contemporary use and future expectations.

Patients who have an acoustic neuroma (vestibular schwannoma) can be managed with observation, open surgical resection, stereotactic radiosurgery, or fractionated radiotherapy. Increasing numbers of patients are choosing radiosurgery over resection for their tumor. In this report we discuss the history of stereotactic radiosurgery, and the evolution in technique that has led to current results with this approach. We discuss the indications for and expectations with the different treatments. The literature on radiosurgery and radiotherapy is reviewed. It is expected that clinical and basic studies will further improve results.

Concurrent sequencing of full-dose CMF chemotherapy and radiation therapy in early breast cancer has no effect on treatment delivery.

With the increasing use of breast-conserving therapy plus systemic chemotherapy for the treatment of early breast cancer, the optimal sequencing of radiation therapy and chemotherapy remains controversial. Sequencing of therapy may influence not only treatment delivery, but control rates, complications and cosmesis. The aim of this study was to evaluate whether concurrent sequencing of standard doses of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) and adjuvant radiation therapy for early breast cancer impacted on optimum treatment delivery. As both an intravenous (i.v.) 3-week regimen and classic (standard) CMF were utilised in this study, both types of CMF were compared. The effect of sequencing on complications and treatment delays were also assessed. 116 patients treated with CMF chemotherapy and adjuvant tangent breast radiation were studied. 73 patients were treated prospectively with concurrent therapy and were retrospectively compared with a matched group of 40 patients treated with sequential or sandwich therapy. All patients had stage 1 or 2 cancers. There were no planned dose reductions introduced for either treatment modality. Concurrent sequencing had no impact on the ability to deliver optimum radiation or chemotherapy doses. There was no significant difference in acute Radiation Therapy Oncology Group (RTOG) skin reactions or complications between the two groups. Although small, there was a significant delay (1.32 days (0-15 versus 0.36 (0-7)) in the concurrent group (P=0.03) in the delivery of radiation therapy. Sequencing had no significant effect on haematological parameters. 'Standard' CMF had a more profound effect on treatment delivery than i.v. CMF (Radiation delay 2.2 days versus 0.26, P=0.002, % chemotherapy delivered 93% versus 99% P=0.000004). At a mean follow-up of 2.6 years, there was no difference in the cosmetic scores between the two groups. Both local and distant control rates were excellent. This study has shown that standard radiation therapy can be delivered safely concurrently with CMF chemotherapy. Whether this approach may lead to better control rates in the future needs further study.

Controversies in the management of multiple brain metastases: the roles of radiosurgery and radiation therapy.

Multiple brain metastases (BrM) are a common challenge to patients with cancer. Tumour resection is used mainly for patients with large tumours that cause acute neurological syndromes. The prognosis, even after treatment with whole brain radiation therapy (WBRT), is poor with average expected survivals less than six months. For this reason, numerous centres have evaluated the role of stereotactic radiosurgery (SRS) in patients with solitary or multiple tumours. We conducted a randomised trial that compared radiosurgery plus WBRT to WBRT alone. The rate of local failure at one year was 100% after WBRT alone but only 8% in patients who had boost radiosurgery. The median time to local failure was six months after WBRT alone in comparison to 36 months after WBRT plus radiosurgery (p=0.0005). The median time to any brain failure was improved in the radiosurgery group (p=0.002). Survival was related to extent of extracranial disease (p=0.02). Combined WBRT and radiosurgery for patients with two to four BrM significantly improves control of brain disease. WBRT alone, for years the standard treatment, does not appear to provide lasting and effective care for most patients. Controversies remain in patient selection, number of BrM suitable for treatment, concomitant management of extracranial disease, and timing of therapy.

Stereotactic radiosurgery for residual neurocytoma. Report of four cases.

The purpose of this report was to review the results of stereotactic radiosurgery in the management of patients with residual neurocytomas after initial resection or biopsy procedures. Four patients underwent stereotactic radiosurgery for histologically proven neurocytoma. Clinical and imaging studies were performed to evaluate the response to treatment. Radiosurgery was performed to deliver doses to the tumor margin of 14, 15, 16, and 20 Gy, depending on tumor volume and proximity to critical adjacent structures. More than 3 years later, imaging studies revealed significant reductions in tumor size. No new neurological deficits were identified at 53, 50, 42, and 38 months of follow up. The authors' initial experience shows that stereotactic radiosurgery appears to be an effective treatment for neurocytoma.

An analysis of the effects of smoking and other cardiovascular risk factors on obliteration rates after arteriovenous malformation radiosurgery.

PURPOSE: To assess the relationships of smoking and other cardiovascular disease risk factors (hypertension, diabetes, hypercholesterolemia, and gender) to rates of radiosurgery-induced obliteration of arteriovenous malformations (AVM). METHODS AND MATERIALS: We evaluated follow-up imaging and clinical data in 329 AVM patients who received gamma knife radiosurgery at the University of Pittsburgh between 1987 and 1994. There were 113 smokers, 29 hypertensives, 5 diabetics, 4 hypercholesterolemics, 159 male patients, and 170 female patients. All patients had regular clinical or imaging follow-up for a minimum of 3 years after radiosurgery. RESULTS: Multivariate analysis showed that smoking had no effect on AVM obliteration (p > 0.43). Hypertension, diabetes, and hypercholesterolemia had no discernible effect on AVM obliteration in this study (p > 0.78). However, females aged 12-49 had a statistically significant lower in-field obliteration rate than males (78% vs. 89%, p = 0.0102). CONCLUSION: Smoking has no effect on AVM obliteration. Hypertension, diabetes, and hypercholesterolemia had no discernible effect in this study. Further study is needed to establish whether estrogen has a vascular protective effect that could partially limit radiosurgical AVM obliteration, as suggested by this study.

Radiotherapy and radiosurgical management of brain metastases.

Out of the various cancer treatment modalities available, radiotherapy is the most commonly used for managing metastatic disease in the brain. Until recent years, this was almost exclusively limited to whole-brain radiotherapy (WBRT). Radiosurgery has emerged as a powerful technique for controlling small to moderate-sized brain metastases (<4 cm in diameter). Tumor control rates with radiosurgery are superior to those with WBRT and appear to equal or surpass those with surgery plus WBRT in most studies. The choice among various radiation management strategies (radiosurgery alone, radiosurgery plus WBRT, or surgery followed by radiotherapy) should be based on the size and location of the brain metastases, the functional and neurologic status of the patient, the type of tumor, the tumor imaging characteristics, and the patient's concerns about the risks and side effects of the proposed treatment.

Does increased nerve length within the treatment volume improve trigeminal neuralgia radiosurgery? A prospective double-blind, randomized study.

PURPOSE: To test the hypothesis that increasing the nerve length within the treatment volume for trigeminal neuralgia radiosurgery would improve pain relief. METHODS AND MATERIALS: Eighty-seven patients with typical trigeminal neuralgia were randomized to undergo retrogasserian gamma knife radiosurgery (75 Gy maximal dose with 4-mm diameter collimators) using either one (n = 44) or two (n = 43) isocenters. The median follow-up was 26 months (range 1-36). RESULTS: Pain relief was complete in 57 patients (45 without medication and 12 with low-dose medication), partial in 15, and minimal in another 15 patients. The actuarial rate of obtaining complete pain relief (with or without medication) was 67.7% +/- 5.1%. The pain relief was identical for one- and two-isocenter radiosurgery. Pain relapsed in 30 of 72 responding patients. Facial numbness and mild and severe paresthesias developed in 8, 5, and 1 two-isocenter patients vs. 3, 4, and 0 one-isocenter patients, respectively (p = 0.23). Improved pain relief correlated with younger age (p = 0.025) and fewer prior procedures (p = 0.039) and complications (numbness or paresthesias) correlated with the nerve length irradiated (p = 0.018). CONCLUSIONS: Increasing the treatment volume to include a longer nerve length for trigeminal neuralgia radiosurgery does not significantly improve pain relief but may increase complications.

Stereotactic radiosurgery of residual or recurrent craniopharyngioma, after surgery, with or without radiation therapy.

This study evaluated the role of stereotactic radiosurgery in the multimodality management of craniopharyngioma patients whose prior therapies failed. Ten consecutive patients (3 males and 7 females) had radiosurgery for craniopharyngioma during a 10-year interval. Their ages ranged from 9 to 64 years (median, 14.5 years). The median interval between diagnosis and radiosurgery was 46.5 months. In total, 12 stereotactic radiosurgical procedures were performed to control the solid component of the tumor (2 intrasellar and 10 suprasellar tumors). The median tumor volume was 1.35 cm3. One to 9 isocenters with different beam diameters were used; the median marginal dose was 16.4 Gy; and the dose to the optic apparatus was limited to less than 8 Gy. Clinical and imaging follow-up data were obtained at a median of 63 months (range, 13-150 months) from radiosurgery. Overall, 7 of 12 tumors became smaller or vanished within a median of 8.5 months. Prior visual defects objectively improved in 6 patients. One patient with prior visual defect deteriorated further and lost vision 9 months after radiosurgery. Multimodality therapy is often necessary for patients with refractory solid and cystic craniopharyngiomas. Stereotactic radiosurgery is a reasonable option in select patients with small recurrent or residual craniopharyngioma.

Shoulder and arm problems after radiotherapy for primary breast cancer.

There is little, if any, difference in disease-free or overall survival for patients with stage I and II breast cancer treated by either breast conservation therapy or mastectomy. With either treatment, there may be cosmetic and functional problems related to arm edema, limited shoulder motion, and shoulder pain. The extent to which factors such as surgery, radiotherapy, systemic therapy, and patient characteristics affect development of arm edema, limited shoulder motion, and shoulder pain is not well documented. We undertook a prospective study of arm edema, limited shoulder motion, and shoulder pain in every patient (N = 331) seen during a 6-month period for follow-up after radiotherapy postlumpectomy or mastectomy for primary breast cancer. Local treatment included lumpectomy and breast irradiation with (n = 232) or without (n = 97) axillary dissection. Ten other women underwent mastectomy and postoperative radiotherapy. Doses to each region treated were 50 Gy in 25 fractions. The operative area was treated with an additional 1,000 Gy in approximately 60% of patients. Twelve patients received axillary irradiation without axillary dissection, and 11 patients received supraclavicular irradiation. Chemotherapy with or without tamoxifen was used in 71 patients and tamoxifen alone was used in 150 patients. One hundred ten patients did not receive any adjuvant therapy. Ipsilateral arm edema occurred in 20 women (6.0%), limited ipsilateral shoulder motion in 5 (1.5%), and ipsilateral shoulder pain in 5 (1.5%). Edema was mild (1+) in 15 patients and moderate (2+) in five patients. Multivariate analysis revealed that the risk of arm edema was significantly increased in black women (p = 0.005, 4/18 versus 16/313 whites) and with mastectomy (p = 0.048, 2/10 versus 18/321 with lumpectomy). There is a low incidence of arm edema, decreased range of motion of the ipsilateral shoulder, and shoulder-arm pain in patients undergoing postlumpectomy or postmastectomy radiotherapy. The risk of arm edema is increased in black women and in patients after mastectomy as opposed to lumpectomy.