John M. Varlotto

Fractionated stereotactic radiotherapy for the treatment of acoustic neuromas: preliminary results.

PURPOSE To evaluate the efficacy and toxicity of fractionated, stereotactic radiotherapy (SRT) for acoustic neuromas. METHODS AND MATERIALS Twelve patients with acoustic neuroma were treated with SRT between June 1992 and October 1994. Follow-up ranged from 16-44 months. Patient age ranged from 27-70 (median: 45). Eight patients were treated with primary SRT and four patients were treated after primary surgical intervention for recurrent [3] or persistent [1] disease. Tumor volumes were 1.2-18.4 cm3 (median: 10.1 cm3). Collimator sizes ranged from 30-50 mm (median: 37.5). Tumors received 1.8 Gy/day normalized to the 95% isodose line. Patients received a minimum prescribed dose of 54 Gy in 27-30 fractions over a 6-week period. RESULTS After a median follow-up of 26.5 months, local control was obtained in 12 out of 12 lesions. Tumor regression was noted in three patients, and tumor stabilization was found in the remaining nine patients. No patient developed a new cranial nerve deficit. One patients developed worsening of preexisting Vth cranial neuropathy and another experienced a decrease in hearing. However, all nine patients with useful hearing prior to SRT maintained useful hearing at last follow-up. CONCLUSIONS Stereotactic radiotherapy provided excellent local control without new cranial nerve deficits. These results must be viewed as tentative in nature because of the small number of patients and the short median follow-up period.

Analysis of tumor control and toxicity in patients who have survived at least one year after radiosurgery for brain metastases.

PURPOSE To better evaluate tumor control and toxicity from radiosurgery for brain metastases, we analyzed these outcomes in patients who had survived at least 1 year after radiosurgery. METHODS AND MATERIALS We evaluated the results of gamma knife stereotactic radiosurgery (SRS) for 208 brain metastases in 137 patients who were followed for a median of 18 months (range 12-122) after radiosurgery. The median patient age was 53 years (range 3-83). Ninety-nine patients had solitary metastases. Thirty-eight had multiple tumors. Sixty-nine patients underwent initial SRS with whole brain radiotherapy (WBRT), 39 had initial SRS alone, and 27 patients had failed prior WBRT. The median treatment volume was 1.9 cm(3) (range 0.05-21.2). The median marginal tumor dose was 16 Gy (range 12-25). The most common histologic types included non-small-cell lung cancer, breast cancer, melanoma, and renal cell carcinoma, which comprised 37.0%, 22.6%, 13.0%, and 9.13% of the lesions, respectively. Forty-five tumors were associated with extensive edema. RESULTS At 1 and 5 years, the local tumor control rate was 89.6% +/- 2.1% and 62.8% +/- 6.9%, distal intracranial relapse occurred in 23% +/- 3.6% and 67.1% +/- 8.7%, and postradiosurgical sequelae developed in 2.8% +/- 1.2% and 11.4% +/- 3.5% of patients, respectively. Multivariate analysis found that local control decreased with tumor volume (p = 0.0002), SRS without WBRT (p = 0.008), and extensive edema (p = 0.024); distal intracranial recurrence correlated with younger patient age (p = 0.0018); and postradiosurgical sequelae increased with increasing tumor volume (p = 0.0085). CONCLUSION Long-term control of brain metastases and complication rates in this selective series of patients surviving >or=1 year after radiosurgery were similar to previously reported actuarial estimates. Large metastases and metastases associated with extensive edema can be difficult to control by radiosurgery, particularly without WBRT.

Extent of Lymphadenectomy and Outcome for Patients With Stage I Nonsmall Cell Lung Cancer

It is uncertain whether lymphadenectomy (LA) affects overall survival (OS) or disease‐free survival (DFS) rates for patients with stage I nonsmall cell lung cancer (NSCLC), as is the optimal number of lymph nodes that should be recovered.

EXTERNAL BEAM IRRADIATION OF CRANIOPHARYNGIOMAS: LONG-TERM ANALYSIS OF TUMOR CONTROL AND MORBIDITY

PURPOSE To delineate the long-term control and morbidity with external beam radiotherapy (EBRT) of craniopharyngiomas. METHODS AND MATERIALS Between 1971 and 1992, 24 craniopharyngioma patients underwent EBRT at the University of Pittsburgh. Most (19 of 24) were treated within 1-3 months after subtotal resection. The other prior surgical procedures were biopsy (n = 2) and gross total resection (n = 1); 2 patients did not undergo any surgical procedure. The median follow-up was 12.1 years. The median patient age was 29 years (range 5-69). The total radiation doses varied from 36 to 70 Gy (median 59.75). The normalized total dose (NTD, biologically equivalent dose given in 2 Gy/fraction [alpha/beta ratio = 2]) varied from 28 to 83 Gy (median 55.35). RESULTS The actuarial survival rate at 10 and 20 years was 100% and 92.3%, respectively. The actuarial local control rate at 10 and 20 years was 89.1% and 54.0%, respectively. No local failures occurred with doses >or=60 Gy (n = 12) or NTDs >or=55 Gy. The complication-free survival rate at 10 and 20 years was 80.1% and 72.1%, respectively. No complications were noted with an NTD of <or=55 Gy. The actuarial survival free from any adverse outcome (recurrence or complication) was 70.1% and 31.8% at 10 and 20 years, respectively. The adverse outcome-free survival appeared optimized (at 73%) with an NTD of 55-63 Gy. Multivariate analysis found that tumor control correlated significantly with the total dose (p = 0.02), treatment complications with NTD (p = 0.008), and adverse outcome with hypopituitarism on presentation (p = 0.03). CONCLUSION We recommend treating craniopharyngioma with 1.6-1.7-Gy dose fractions to 60 Gy to optimize outcome from EBRT.

Factors Associated With Local and Distant Recurrence and Survival in Patients With Resected Nonsmall Cell Lung Cancer

This study assessed the impact of surgical, histopathologic and patient‐related factors on the risks of local and distant recurrence and overall survival for patients with stages I through IIIA nonsmall cell lung carcinoma (NSCLC) undergoing definitive resection with or without adjuvant chemotherapy.

Matched-pair and propensity score comparisons of outcomes of patients with clinical stage i non-small cell lung cancer treated with resection or stereotactic radiosurgery

Stereotactic body radiotherapy (SBRT) is an alternative to surgery for clinical stage I non–small cell lung cancer (NSCLC), but comparing its effectiveness is difficult because of differences in patient selection and staging.

Should Large Cell Neuroendocrine Lung Carcinoma be Classified and Treated as a Small Cell Lung Cancer or with Other Large Cell Carcinomas

Background: To compare the presenting and prognostic characteristics of patients with large cell neuroendocrine lung cancer (LCNELC) with those of patients with small cell lung cancer (SCLC) or other large cell carcinomas (OLCs) and to compare overall survival (OS) and lung cancer-specific survival (LCSS) rates for patients undergoing definitive resection without radiotherapy (S-NoRT). Methods: The Surveillance Epidemiology and End Results Database-17 from 2001 to 2007 was used. Differences between population characteristics were compared using &khgr;2 and Wilcoxon tests. The log-rank test and Cox models were used to compare differences in OS and LCSS. Results: There were 1211 patients with LCNELC (324 in the S-NoRT group), 8295 patients with OLC (1120 S-NoRT), and 35,304 patients with SCLC (355 S-NoRT). The proportion of all large cell carcinomas constituted by LCNELC increased from 8 to 21% during the study period; and the proportion of patients with large cell carcinoma undergoing S-NoRT increased from 16 to 26%. Presenting and histopathologic characteristics and treatment factors of patients undergoing S-NoRT for patients with LCNELC were more similar to those of patients with OLC than to those with SCLC. OS and LCSS rates for patients with LCNELC undergoing resection without radiation were similar to those of patients with OLC and better than those for patients with SCLC, but the differences were not statistically significant on multivariate analysis. Conclusions: The clinical, histopathologic, and biologic features of LCNELC are more similar to OLC than to SCLC. Therefore, LCNELC should continue to be classified and treated as a large cell carcinoma.

Hypertonic Treatment during Premature Chromosome Condensation Allows Visualization of Interphase Chromosome Breaks Repaired with Fast Kinetics in Irradiated CHO Cells

A class of interphase chromosome breaks was visualized in irradiated (10 Gy) plateau-phase CHO cells after treatment (2-30 min) in hypertonic (500 mM NaCl) growth medium during the period normally allowed for chromosome condensation, in the premature chromosome condensation (PCC) assay. Rejoining of this class of interphase chromosome breaks was fast (t1/2 = 1.5 min) compared to the rejoining of interphase chromosome breaks normally observed in the absence of hypertonic treatment (t1/2 = 76 min), suggesting that they are formed from a different subset of precursor DNA lesions. A fast (t1/2fast = 12 min) and a slow (t1/2slow = 71 min) component were also observed in the rejoining of radiation-induced (50 Gy) DNA double-strand breaks (DSBs), as measured by pulsed-field gel electrophoresis. We propose that fast-repairing DSBs are the precursor lesions underlying the fast-repairing interphase chromosome breaks observed in these experiments. Slowly repairing DSBs are postulated to be the precursor lesions underlying the slowly repairing interphase chromosome breaks visualized using regular protocols for PCC. The visualization of fast-repairing interphase chromosome breaks achieved in these experiments is assumed to be due to a destabilization of chromatin by the hypertonic medium. This chromatin destabilization may cause either an inhibition of the rejoining of the fast component of DSBs during the period allowed for PCC or a transformation of a defined subset of fast-repairing DSBs into chromosome breaks. The latter hypothesis allows a more consistent interpretation of the available results. Transformation of a defined subset of fast-repairing DSBs to interphase chromosome breaks may be equivalent to damage fixation, and may correspond to the fixation of a form of PLD (beta-PLD) sensitive to treatment in hypertonic medium.

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.

Hypertonic Treatment Does Not Affect the Radiation Yield of Interphase Chromosome Breaks in DNA Double-Strand Break Repair-Deficient xrs-5 Cells

A DNA double-strand break (DSB) repair-deficient CHO cell line, xrs-5, was used to evaluate the effect of hypertonic treatment on the radiation yield of interphase chromosome breaks, as visualized by means of premature chromosome condensation (PCC). For this purpose, interphase chromosome breaks were measured in plateau-phase G1 cells after exposure to 10 Gy X rays using either the standard protocol for PCC induction or a revised protocol that includes a brief (20 min) treatment in hypertonic medium (500 mM NaCl) during chromosome condensation. Experiments at the chromosome level were complemented by experiments at the DNA and the cellular level performed under similar postirradiation conditions. The results obtained were compared to those reported previously for CHO cells. Radiation yields of interphase chromosome breaks, as measured using standard protocols for PCC induction, were higher in xrs-5 than in CHO cells. However, the yields became similar between the two cell lines when a 20-min incubation in hypertonic medium was introduced immediately after fusion with mitotic cells. This equalization was due to the fact that incubation in hypertonic medium did not affect the radiation yield of interphase chromosome breaks in xrs-5 cells but increased it in CHO cells to levels similar to those measured in xrs-5 cells. This result suggests that xrs-5 cells constitutively express as interphase chromosome breaks a subset of DSBs which in repair-proficient CHO cells requires incubation in hypertonic medium for transformation to interphase chromosome breaks. Rejoining of DSBs, when measured in isotonic medium, was incomplete in xrs-5 cells compared to CHO cells. Rejoining of DSBs normally repaired in xrs-5 cells was completely inhibited during treatment in hypertonic medium. Postirradiation treatment in hypertonic medium affected the survival of xrs-5 cells only modestly, suggesting that the sector of PLD (beta-PLD) which required treatment in hypertonic medium for fixation in repair-proficient CHO cells is fixed constitutively in xrs-5 cells. These results are in agreement with a model developed to interpret results obtained in similar experiments with CHO cells (Iliakis et al., Radiat. Res 135, 160-170, 1993). The model postulates that potentiation in CHO cell killing induced by hypertonic treatment is caused by the transformation of a subset of fast-repairing DSBs to irreparable interphase chromosome breaks and assumes that this transformation is equivalent to fixation of beta-PLD.(ABSTRACT TRUNCATED AT 400 WORDS)