Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study.

Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood-brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10-300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9-13.5) and for the breast cancer subgroup was 7.7 mo (2.8-15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3-3.8) and 4.9 mo (4.2-5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.

Multidisciplinary therapy of stage IIIA non-small-cell lung cancer: long-term outcome of chemoradiation with or without surgery.

BACKGROUND: Stage IIIA non-small-cell lung cancer (NSCLC) is highly heterogeneous due to differences in the size of the primary tumor and the extent and location of nodal disease. Although the addition of surgery to chemoradiation did not improve overall survival (OS) for stage IIIA patients in a randomized intergroup trial (INT 0139), subset analyses of the trial suggest that a trimodality approach incorporating lobectomy may be superior to bimodality therapy with chemoradiation alone. METHODS: We analyzed the outcomes of patients with stage IIIA NSCLC (T3N1, T1-3N2) treated at our center between January 2000 and December 2008. We compared OS for those undergoing definitive chemoradiation to those undergoing chemoradiation followed by either lobectomy or pneumonectomy. Demographic variables were balanced by propensity score analysis method. RESULTS: In our analysis of 249 patients, the median age was 65 years, 43% were men, and 96.5% had N2 disease. Chemoradiation followed by lobectomy yielded superior OS compared with chemoradiation (median OS 39 months vs 22 months, P = .038 after propensity score adjustment). There was no significant survival benefit for pneumonectomy over chemoradiation (median survival 28 months vs 22 months, P = .534). CONCLUSIONS: Our data corroborate the findings of the INT 0139 trial. We propose that a formal randomized trial be performed comparing chemoradiation followed by lobectomy vs definitive chemoradiation in patients with stage IIIA disease whose tumors are resectable by lobectomy. Our data do not support the incorporation of pneumonectomy in the management of stage IIIA patients with N2 disease.

Absolute lymphocyte count: a potential prognostic factor for Merkel cell carcinoma.

BACKGROUND: Absolute lymphocyte count (ALC) is a laboratory value commonly obtained during workup of patients with Merkel cell carcinoma (MCC). OBJECTIVE: We report the prognostic impact of ALC as a surrogate of immune status in MCC. METHODS: A complete blood cell count was available for 64 patients with MCC in the month before definitive surgery, chemotherapy, or radiation. Statistical analysis was performed with classification and regression tree analysis, log rank test, and Cox model. RESULTS: Median overall survival (OS) for the cohort was 97 months. Median OS for patients with an ALC less than 1.1 k/mm(3) was 18.8 versus 110.1 months for those with ALC greater than or equal to 1.1 k/mm(3) (P = .002, hazard ratio 0.29). Multivariate analysis of OS controlling for ALC, sex, stage, adjuvant chemotherapy, hematologic malignancy, and immunosuppression demonstrated ALC as a prognostic factor (P = .03). Disease-free survival at 36 months for ALC less than 1.1 k/mm(3) was 26.9% versus 64.4% for those with ALC greater than or equal to 1.1 k/mm(3) (P = .01). ALC was not a significant predictor for disease-free survival on multivariate analysis (P = .12). LIMITATIONS: This is a single-institution retrospective data set. CONCLUSION: ALC is associated with OS but not disease-free survival in MCC using a threshold of less than 1.1 k/mm(3). This test may provide additional prognostic information for patients with MCC.

Target repositional accuracy and PTV margin verification using three-dimensional cone-beam computed tomography (CBCT) in stereotactic body radiotherapy (SBRT) of lung cancers.

The purpose of this study was to assess target repositional accuracy with respect to the bony structures using daily CBCT, and to validate the planning target volume (PTV) margin used in the lung SBRT. All patients underwent 4D CT scanning in preparation for lung SBRT. The internal target volume (ITV) was outlined from the reconstructed 4D data using the maximum-intensity projection (MIP) algorithm. A 6 mm margin was added to the ITV to create the PTV. Conformal treatment planning was performed on the helical images, to which the MIP images were fused. Prior to each treatment, CBCT was taken after a patient was set up in the treatment position. The CBCT images were fused with the simulation CT based on the bony anatomy, in order to derive setup errors and separate them from the tumor repositional errors. The treating physician then checked and modified the alignment based on target relocalization within the PTV. The shifts determined in such a method were recorded and the subtractions of these shifts with respect to the corresponding setup errors were defined as the target relocalization accuracy. Our study of 36 consecutive patients, treating 38 targets for a total of 153 fractions shows that, after setup error correction, the target repositional accuracy followed a normal distribution with the mean values close to 0 in all directions, and standard deviations of 0.25 cm in A-P, 0.24 cm in Lat, and 0.28 cm in S-I directions, respectively. The probability of having the shifts ? 0.6 cm is less than 0.8% in A-P, 0.6% in Lat, and 1.7 % in S-I directions. For the patient population studied, the target centroid position relative to the bony structures changed minimally from day to day. This demonstrated that the PTV margin that is designed on the MIP image-based ITV was adequate for lung SBRT.

Young age is not associated with increased local recurrence for DCIS treated by breast-conserving surgery and radiation.

BACKGROUND: We report local recurrence (LR) after breast-conserving surgery and radiation (BCS + RT) for ductal carcinoma in situ (DCIS) to determine outcomes for patients aged

Bilateral granulosa cell tumors: a novel malignant manifestation of multiple endocrine neoplasia 1 syndrome found in a patient with a rare menin in-frame deletion.

INTRODUCTION: Multiple endocrine neoplasia 1 (MEN1) is a cancer syndrome resulting from mutations of the MEN1 gene. The syndrome is characterized by neoplasia of the parathyroid and pituitary glands, and malignant tumors of the endocrine pancreas. Other manifestations include benign lipomas, angiofibromas, and carcinoid tumors commonly originating in the colon, thymus, and lung. This is the first report of MEN1 syndrome manifesting as bilateral granulosa cell ovarian tumors, and which is associated with a rare intronic mutation of the MEN1 gene. CASE REPORT: A 41-year-old woman presented with abdominal pain, increasing abdominal girth, and dysmenorrhea. Ultrasound demonstrated enlarged ovaries and uterine fibroids. After an exploratory laparotomy, she subsequently underwent bilateral salpingo-oophorectomy with hysterectomy where the pathology revealed bilateral cystic granulosa cell tumors of the ovaries. Additional workup including computed tomography imaging discovered a thymic mass, which the pathology showed was malignant, along with a pancreatic mass suspicious for a neuroendocrine tumor. Hyperparathyroidism was also discovered and was found to be secondary to a parathyroid adenoma. Genetic testing revealed an exceedingly rare mutation in the MEN1 gene (c.654 + 1 G>A). DISCUSSION: Mutations of the menin gene leading to MEN1 syndrome are classically nonsense or missense mutations producing a dysfunctional protein product. Recently, researchers described a novel mutation of MEN1 (c.654 + 1 G>A) in a male proband meeting the criteria for clinical MEN1 syndrome. Functional analysis performed on the stable mutant protein showed selective disruption of the transforming growth factor beta signaling pathway, yet it maintained its wild-type ability to inhibit nuclear factor kappa B and to suppress JunD transcriptional activity. CONCLUSION: To our knowledge, this is the first report of MEN1 syndrome associated with bilateral granulosa cell malignancy. We postulate that this presentation may be due to the novel menin gene mutation recently described.

Predictors and management of chest wall toxicity after lung stereotactic body radiotherapy.

Stereotactic body radiotherapy is the preferred treatment modality for patients with inoperable early stage lung cancer. Chest wall toxicity is a potentially dose limiting side effect and may include fractures or pain secondary to treatment. The pathophysiology of these symptoms is unclear although it is presumed that radiation may alter the bone's normal tissue environment, affecting maintenance and remodeling. Chest wall pain is likely neuropathic secondary to injury to the intercostal nerves. Identifying patients with chest wall toxicity can be difficult due to the varying definitions of toxicity as well as heterogeneous contouring guidelines. Multiple studies have demonstrated a correlation between treatment factors and the incidence of chest wall toxicity. An increase in dose and treatment volume appear to be the most consistent radiation factors associated with toxicity. Patient factors such as body mass index, female gender, tumor location, and age have also been correlated with an increased likelihood of developing side effects. Management of chest wall toxicity is typically conservative using analgesic medications although surgical intervention may be required for displaced fractures. In this review, we examine the treatment, patient, and tumor factors predictive for chest wall toxicity and the implications for the treating physician.

A better prognosis for Merkel cell carcinoma of unknown primary origin.

BACKGROUND: There is limited evidence that Merkel cell carcinoma (MCC) arising from a nodal basin without evidence of a primary cutaneous (PC) site has better prognosis. We present our experience at 2 tertiary care referral centers with stage III MCC with and without a PC site. METHODS: Fifty stage III MCC patients were identified between 1996 and 2011. Clinical data were analyzed, with primary endpoints being disease-free survival and overall survival. RESULTS: Of stage III patients, 34 patients presented with a PC site and 16 patients with an unknown primary (UP) site. Treatment strategies varied; of patients with UP vs. PC sites, 25% vs. 44% underwent combined regional lymphadenectomy and radiation, with an additional 25% vs. 15% receiving chemotherapy. The median disease-free survival for a UP site was not reached vs. 15 months for a PC site (hazards ratio = .48, P = .18). The median overall survival for a UP site was not reached vs 21 months for a PC site (hazards ratio = .34, P = .03). Multivariate analysis showed that UP status was a significant factor in overall survival (P = .002). CONCLUSIONS: Stage III MCC with a UP site portends a better prognosis than MCC with a PC site.

Lacrimal gland lymphoma: Role of radiation therapy.

BACKGROUND: To report the clinical and treatment outcome of patients with lacrimal gland lymphoma (LGL) treated with radiation therapy (RT) at Fox Chase Cancer Center, Philadelphia, PA, USA. MATERIALS AND METHODS: Institutional review board approved retrospective chart review of eight patients and literature review. RESULTS: The study patients included six males and two females with a mean age of 70 years (range 58-88 years). The mean follow-up period was 23 months (range 3-74 months). Four patients had mucosa-associated lymphoid tissue (50%) lymphoma and four patients had other non-Hodgkin's lymphoma variants. Four patients had bilateral disease (50%). Four patients had primary LGL (stages I-IIAE, 50%) and four had LGL as part of systemic lymphoma (stage IVAE, 50%). The median RT dose was 2987 cGy (range 2880-3015 cGy). All patients had complete response to RT with symptomatic relief. Minimal dry eye was seen in all patients. There were no late effects such as corneal ulcer, radiation retinopathy, maculopathy, papillopathy, or secondary neovascular glaucoma. CONCLUSIONS: RT alone is an extremely effective treatment in the curative management of localized LGL and provides durable, local control of secondary LGL.

Radiation therapy for pituitary metastasis: report of four cases.

AIMS AND BACKGROUND: To report the clinical outcomes of four patients with pituitary metastases treated with radiotherapy. METHODS: Retrospective chart review of four cases. RESULTS: The mean age of the patients was 66 years; two were women and two were men. The mean duration of symptoms at initial presentation of the primary tumor was 2.25 months. The location of the primary tumor was the breast in one case and the lung in three. Magnetic resonance imaging of the brain revealed sellar masses in all cases. The mean interval between the primary tumor diagnosis and the development of pituitary metastases was 22.5 months. The metastases were treated with radiation therapy (palliative/stereotactic/intensity modulated) at a mean dose of 3219 cGy. At the last follow-up, three patients were dead and one was alive. CONCLUSIONS: Treatment with three-dimensional conformal radiotherapy or stereotactic radiotherapy is a suitable non-surgical option for patients with pituitary metastases.

Hypoxic prostate/muscle PO2 ratio predicts for outcome in patients with localized prostate cancer: long-term results.

PURPOSE: To correlate tumor oxygenation status with long-term biochemical outcome after prostate brachytherapy. METHODS AND MATERIALS: Custom-made Eppendorf PO(2) microelectrodes were used to obtain PO(2) measurements from the prostate (P), focused on positive biopsy locations, and normal muscle tissue (M), as a control. A total of 11,516 measurements were obtained in 57 men with localized prostate cancer immediately before prostate brachytherapy was given. The Eppendorf histograms provided the median PO(2), mean PO(2), and % <5 mm Hg or <10 mm Hg. Biochemical failure (BF) was defined using both the former American Society of Therapeutic Radiation Oncology (ASTRO) (three consecutive raises) and the current Phoenix (prostate-specific antigen nadir + 2 ng/mL) definitions. A Cox proportional hazards regression model evaluated the influence of hypoxia using the P/M mean PO(2) ratio on BF. RESULTS: With a median follow-up time of 8 years, 12 men had ASTRO BF and 8 had Phoenix BF. On multivariate analysis, P/M PO(2) ratio <0.10 emerged as the only significant predictor of ASTRO BF (p = 0.043). Hormonal therapy (p = 0.015) and P/M PO(2) ratio <0.10 (p = 0.046) emerged as the only independent predictors of the Phoenix BF. Kaplan-Meier freedom from BF for P/M ratio <0.10 vs. ≥0.10 at 8 years for ASTRO BF was 46% vs. 78% (p = 0.03) and for the Phoenix BF was 66% vs. 83% (p = 0.02). CONCLUSIONS: Hypoxia in prostate cancer (low mean P/M PO(2) ratio) significantly predicts for poor long-term biochemical outcome, suggesting that novel hypoxic strategies should be investigated.

Use of a conventional low neck field (LNF) and intensity-modulated radiotherapy (IMRT): no clinical detriment of IMRT to an anterior LNF during the treatment of head-and neck-cancer.

PURPOSE: To determine differences in clinical outcomes using intensity-modulated radiotherapy (IMRT) or a standard low neck field (LNF) to treat low neck. METHODS AND MATERIALS: This is a retrospective, single-institution study. Ninety-one patients with squamous cell carcinoma of the head and neck were treated with curative intent. According to physician preference, some patients were treated with LNF (Planning Target Volume 3) field using a single anterior photon field matched to the IMRT field. Field junctions were not feathered. The endpoints were time to failure and use of a percutaneous endoscopic gastrostomy (PEG) tube (as a surrogate of laryngeal edema causing aspiration), and analysis was done with χ(2) and log-rank tests. RESULTS: Median follow-up was 21 months (range, 2-89 months). Median age was 60 years. Thirty-seven patients (41%) were treated with LNF, 84% were Stage III or IV. A PEG tube was required in 30%, as opposed to 33% without the use of LNF. Node 2 or 3 neck disease was treated more commonly without LNF (38% vs. 24%, p = 0.009). Failures occurred in 12 patients (13%). Only 1 patient treated with LNF failed regionally, 4.5 cm above the match line. The 3-year disease-free survival rate was 87% and 79% with LNF and without LNF, respectively (p = 0.2), and the 3-year LR failure rate was 4% and 21%, respectively (p = 0.04). CONCLUSIONS: Using LNF to treat the low neck did not increase the risk of regional failure "in early T and early N diseases" or decrease PEG tube requirements.

Increased recurrences using intensity-modulated radiation therapy in the postoperative setting.

PURPOSE: To determine the pattern of failures following intensity modulated radiation therapy for head and neck cancer. MATERIAL AND METHODS: A retrospective single institution study. Between May 2001 and June 2008, 176 patients with head and neck cancer were treated with intensity modulated radiation therapy at Fox Chase Cancer Center. Ninety-five (54%) were squamous cell carcinoma treated with curative intent. Tumor and nodal stage, tobacco history, definitive versus postoperative therapy (PORT), addition of chemotherapy and RT duration were analyzed for association with patterns of failure. In patients treated with definitive radiation, high-risk PTV (PTV1) was prescribed to 70 Gy and low-risk PTV (PTV2) to 56 Gy. In the PORT setting, PTV1 was prescribed to 60 to 66 Gy and PTV2 to 54 Gy. Patterns of failure were assessed. Local failure (LF) was defined as the persistence of disease or recurrence within PTV1, marginal failure as recurrence at the region of high-dose falloff, and regional failure as nodal recurrence within PTV2. RESULTS: Median follow-up was 20 months (range: 1-117). Median age was 60 years (range: 28-88), with 80% smokers and 81% stage III or IV. PORT was given to 29% and 71% were treated definitively, with concurrent Cisplatin used in the majority. Three-year local and locoregional (LR) failure rates were 9% and 16%, respectively. Failures occurred in 14 patients: 8 local, 3 regional, 1 LR, and 2 distant. Five of the 8 LF and all 3 marginal failures were observed in PORT cohort. On univariate analysis, the only predictor of LF was the use of PORT (P = 0.06). LR control was 66% for PORT versus 87%, 97% for definitive RT and chemoRT. CONCLUSIONS: Local, regional failures were more common following PORT related to an increased risk of marginal failures.