Blood-based biomarkers for malignant gliomas.

Malignant gliomas remain incurable and present unique challenges to clinicians, radiologists and clinical and translational investigators. One of the major problems in treatment of these tumors is our limited ability to reliably assess tumor response or progression. The most frequently used neuro-imaging studies (contrast-enhanced MRI and CT) rely on changes of blood-brain barrier (BBB) integrity, providing only an indirect assessment of tumor burden. In addition, the BBB can be altered by commonly used interventions including radiation, glucocorticoids and vascular endothelial growth factor inhibitors, further complicating the interpretation of scans. Newer radiologic techniques including PET and magnetic resonance spectroscopy are theoretically promising but thus far have not meaningfully changed the assessment of patients with malignant gliomas. A tumor-specific, blood-based biomarker would be of immediate use to clinicians and investigators if sufficiently sensitive and specific. This review discusses the potential utility of such a biomarker, the general classes of tumor-derived blood-based biomarkers and it summarizes the currently available data on circulating tumor cells, circulating nucleic acids and circulating proteins in patients with malignant gliomas. It is unclear which marker or marker class appears to be the most promising for these tumors. This article provides thoughts on how novel candidate blood-based markers could be discovered and tested in a more comprehensive way and why these efforts should be among the top priorities in neuro-oncologic research in the coming years.

The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells.

PURPOSE: Severe treatment-related lymphopenia (TRL) occurs in 40% of patients with high grade gliomas (HGG) receiving glucocorticoids, temozolomide, and radiation. This occurs following radiation, persists for months, and is associated with reduced survival. As all three treatment modalities are lymphotoxic, this study was conducted to estimate the radiation dose that lymphocytes receive passing through the radiation field and if this could explain the observed TRL. MATERIALS AND METHODS: A typical glioblastoma plan (8-cm tumor, 60 Gy/30 fractions) was constructed using the Pinnacle™ radiation planning system. Radiation doses to circulating cells (DCC) were analyzed using MatLab™. The primary endpoints were mean DCC and percent of circulating cells receiving ≥0.5 Gy. The model was also used to study how changes in target volumes (PTV), dose rates, and delivery techniques affect DCC. RESULTS: The modeling determined that while a single radiation fraction delivered 0.5 Gy to 5% of circulating cells, after 30 fractions 99% of circulating blood had received ≥0.5 Gy. The mean DCC was 2.2 Gy and was similar for IMRT, 3D-conformal techniques, and different dose rates. Major changes in PTV size affected mean DCC and percent of circulating cells receiving ≥0.5 Gy. CONCLUSIONS: Standard treatment plans for brain tumors deliver potentially lymphotoxic radiation doses to the entire circulating blood pool. Altering dose rates or delivery techniques are unlikely to significantly affect DCC by the end of treatment. Novel approaches are needed to limit radiation to circulating lymphocytes given the association of lymphopenia with poorer survival in patients with HGG.

Analysis of local control in patients receiving IMRT for resected pancreatic cancers.

PURPOSE: Intensity-modulated radiotherapy (IMRT) is increasingly incorporated into therapy for pancreatic cancer. A concern regarding this technique is the potential for geographic miss and decreased local control. We analyzed patterns of first failure among patients treated with IMRT for resected pancreatic cancer. METHODS AND MATERIALS: Seventy-one patients who underwent resection and adjuvant chemoradiation for pancreas cancer are included in this report. IMRT was used for all to a median dose of 50.4 Gy. Concurrent chemotherapy was 5-FU-based in 72% of patients and gemcitabine-based in 28%. RESULTS: At median follow-up of 24 months, 49/71 patients (69%) had failed. The predominant failure pattern was distant metastases in 35/71 patients (49%). The most common site of metastases was the liver. Fourteen patients (19%) developed locoregional failure in the tumor bed alone in 5 patients, regional nodes in 4 patients, and concurrently with metastases in 5 patients. Median overall survival (OS) was 25 months. On univariate analysis, nodal status, margin status, postoperative CA 19-9 level, and weight loss during treatment were predictive for OS. On multivariate analysis, higher postoperative CA19-9 levels predicted for worse OS on a continuous basis (p < 0.01). A trend to worse OS was seen among patients with more weight loss during therapy (p = 0.06). Patients with positive nodes and positive margins also had significantly worse OS (HR for death 2.8, 95% CI 1.1-7.5; HR for death 2.6, 95% CI 1.1-6.2, respectively). Grade 3-4 nausea and vomiting was seen in 8% of patients. Late complication of small bowel obstruction occurred in 4 (6%) patients. CONCLUSIONS: This is the first comprehensive report of patterns of failure among patients treated with adjuvant IMRT for pancreas cancer. IMRT was not associated with an increase in local recurrences in our cohort. These data support the use of IMRT in the recently activated EORTC/US Intergroup/RTOG 0848 adjuvant pancreas trial.

Severity, etiology and possible consequences of treatment-related lymphopenia in patients with newly diagnosed high-grade gliomas.

Lymphopenia is a common consequence of therapy for malignant glioma. Current standard therapy includes corticosteroids, temozolomide and radiation therapy, all of which are toxic to lymphocytes. The resulting immunosuppression has serious clinical consequences. Decreased lymphocyte counts can result in opportunistic infections, decreased efficacy of immunotherapy and reduced overall survival. The exact mechanisms underlying the association between decreased survival and lymphopenia in malignant glioma patients are unclear. However, as lymphocytes are key effector cells in the immune response to cancer, it is likely that depleting their numbers renders the immune system less effective at eliminating malignant cells. Currently, no strategies exist for the prevention or reversal of treatment-related immunosuppression in malignant glioma patients, although there are several promising theoretical approaches. This article reviews the current state of knowledge regarding the severity, etiology and possible consequences of treatment-related lymphopenia in patients with malignant glioma.

Primary tumor volume is an important predictor of clinical outcomes among patients with locally advanced squamous cell cancer of the head and neck treated with definitive chemoradiotherapy.

PURPOSE: The tumor volume has been established as a significant predictor of outcomes among patients with head-and-neck cancer undergoing radiotherapy alone. The present study attempted to add to the existing data on tumor volume as a prognostic factor among patients undergoing chemoradiotherapy. METHODS AND MATERIALS: A total of 78 patients who had undergone definitive chemoradiotherapy for Stage III-IV squamous cell cancer of the hypopharynx, oropharynx, and larynx were identified. The primary tumor volumes were calculated from the treatment planning computed tomography scans, and these were correlated to the survival and tumor control data obtained from the retrospective analysis. RESULTS: The interval to progression correlated with the primary tumor volume (p = .007). The critical cutoff point for the tumor volume was identified as 35 cm(3), and patients with a tumor volume <35 cm(3) had a significantly better prognosis than those with a tumor volume >35 cm(3) at 5 years (43% vs. 71%, p = .010). Longer survival was also correlated with smaller primary tumor volumes (p = .022). Similarly, patients with a primary tumor volume <35 cm(3) had a better prognosis in terms of both progression-free survival (61% vs. 33%, p = .004) and overall survival (84% vs. 41%, p = < .001). On multivariate analysis, the primary tumor volume was the best predictor of recurrence (hazard ratio 4.7, 95% confidence interval 1.9-11.6; p = .001) and survival (hazard ratio 10.0, 95% confidence interval 2.9-35.1; p = < .001). In contrast, the T stage and N stage were not significant factors. Analysis of variance revealed that tumors with locoregional failure were on average 21.6 cm(3) larger than tumors without locoregional failure (p = .028) and 27.1-cm(3) larger than tumors that recurred as distant metastases (p = .020). CONCLUSION: The results of our study have shown that the primary tumor volume is a significant prognostic factor in patients with advanced cancer of the head and neck undergoing definitive chemoradiotherapy and correlated with the treatment outcomes better than the T or N stage.

Impact of early percutaneous endoscopic gastrostomy tube placement on nutritional status and hospitalization in patients with head and neck cancer receiving definitive chemoradiation therapy.

BACKGROUND: This study analyzed the impact of timing of percutaneous endoscopic gastrostomy (PEG) tube placement on clinical endpoints in patients undergoing concurrent chemoradiation therapy (CRT). METHODS: In all, 111 patients who underwent CRT for locally advanced squamous cell carcinoma of the head and neck (SCCHN) were retrospectively analyzed to determine the effect of timing of PEG placement on weight loss, hospitalizations, and rates of PEG complications/dependence. RESULTS: Early PEG tube placement was correlated to reductions in weight loss during CRT (p < .001, R = 0.495), hospitalization for nutritional deficits (p = .011, R = 0.262), and magnitude of persistent weight loss at 6 weeks post-CRT (p = .003, R = 0.347). Disease control was the only predictor of PEG dependence. No differences were seen in PEG complication or dependence rates with earlier placement. CONCLUSIONS: The results of our series show that patients with locally advanced SCCHN undergoing definitive CRT may derive significant clinical benefit from the early placement of PEG tubes for nutritional supplementation.

Treatment of glioblastoma in "elderly" patients.

OPINION STATEMENT: The number of patients over 65 with newly diagnosed glioblastoma is anticipated to increase significantly in coming decades as a result of demographic shifts in the United States. Older patients with this disease have a significantly worse life expectancy compared with patients under 65. Mounting clinical evidence suggests that fit elderly patients with glioblastoma benefit from the addition of temozolomide to standard surgery and radiation. As a result, for healthy patients over 65 we recommend maximal surgical debulking followed by involved-field radiotherapy (60 Gy in 30 fractions) with concurrent temozolomide (75 mg/m(2)/day) and 6 months of adjuvant temozolomide (150-200 mg/m(2)/day for five consecutive days/month). Patients over 65 with newly diagnosed or recurrent glioblastoma should also be considered for inclusion in clinical trials. MGMT is a validated prognostic marker in patients over 65 and may be useful in clinical decision-making in frail elderly patients. Age alone should not be a factor in deciding how patients with newly diagnosed glioblastoma should be treated.

Factors impacting volumetric white matter changes following whole brain radiation therapy.

Whole brain radiation therapy (WBRT) is one of the most effective modalities for treatment of brain metastases. With increasing cancer control there is growing concern regarding the long-term effects of treatment. These effects are seen as white matter change (WMC) on brain MRI. Severity of WMC is implicated in cognitive and functional decline in many patient groups. Our objective was to identify clinical factors associated with greater accumulation of WMC following WBRT. Through retrospective review of serial MRIs obtained from 30 patients surviving greater than 1 year after WBRT, treated at a single institution between 2002 and 2007, we calculated volumetric WMC over time using segmentation software. Changes related to tumor, secondary effects, surgery or radiosurgery were excluded. Factors that influenced the rate of WMC accumulation were identified through multivariate analysis. Following WBRT, patients accumulated WMC at an average rate of 0.07% of total brain volume per month. In multivariate analyses, greater rates of accumulation were independently associated with older age (ß = 0.004, p < .0001), poor levels of glycemic control (ß = 0.048, p < .0001) and hypertension diagnosis (ß = 0.084, p < .0001). Long-term survivors of cancer allow assessment of late effects of treatment modalities. Radiation injury appears to be related to a steady rate of white matter damage over time, as indicated by progressive accumulation of WMC. Our results suggest that rate of WMC accumulation is enhanced by parameters such as hyperglycemia and hypertension. This has significant clinical impact by clearly identifying hyperglycemia, steroid-induced hyperglycemia, and other vascular risk factors as targets for intervention to decrease WMC in patients receiving WBRT.

Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers.

PURPOSE: Among patients with upper abdominal malignancies, intensity-modulated radiation therapy (IMRT) can improve dose distributions to critical dose-limiting structures near the target. Whether these improved dose distributions are associated with decreased toxicity when compared with conventional three-dimensional treatment remains a subject of investigation. METHODS AND MATERIALS: 46 patients with pancreatic/ampullary cancer were treated with concurrent chemoradiation (CRT) using inverse-planned IMRT. All patients received CRT based on 5-fluorouracil in a schema similar to Radiation Therapy Oncology Group (RTOG) 97-04. Rates of acute gastrointestinal (GI) toxicity for this series of IMRT-treated patients were compared with those from RTOG 97-04, where all patients were treated with three-dimensional conformal techniques. Chi-square analysis was used to determine if there was a statistically different incidence in acute GI toxicity between these two groups of patients. RESULTS: The overall incidence of Grade 3-4 acute GI toxicity was low in patients receiving IMRT-based CRT. When compared with patients who had three-dimensional treatment planning (RTOG 97-04), IMRT significantly reduced the incidence of Grade 3-4 nausea and vomiting (0% vs. 11%, p = 0.024) and diarrhea (3% vs. 18%, p = 0.017). There was no significant difference in the incidence of Grade 3-4 weight loss between the two groups of patients. CONCLUSIONS: IMRT is associated with a statistically significant decrease in acute upper and lower GI toxicity among patients treated with CRT for pancreatic/ampullary cancers. Future clinical trials plan to incorporate the use of IMRT, given that it remains a subject of active investigation.

Lack of evidence for low-LET radiation induced bystander response in normal human fibroblasts and colon carcinoma cells.

PURPOSE: To investigate radiation-induced bystander responses and to determine the role of gap junction intercellular communication and the radiation environment in propagating this response. MATERIALS AND METHODS: We used medium transfer and targeted irradiation to examine radiation-induced bystander effects in primary human fibroblast (AG01522) and human colon carcinoma (RKO36) cells. We examined the effect of variables such as gap junction intercellular communication, linear energy transfer (LET), and the role of the radiation environment in non-targeted responses. Endpoints included clonogenic survival, micronucleus formation and foci formation at histone 2AX over doses ranging from 10-100 cGy. RESULTS: The results showed no evidence of a low-LET radiation-induced bystander response for the endpoints of clonogenic survival and induction of DNA damage. Nor did we see evidence of a high-LET, Fe ion radiation (1 GeV/n) induced bystander effect. However, direct comparison for 3.2 MeV alpha-particle exposures showed a statistically significant medium transfer bystander effect for this high-LET radiation. CONCLUSIONS: From our results, it is evident that there are many confounding factors influencing bystander responses as reported in the literature. Our observations reflect the inherent variability in biological systems and the difficulties in extrapolating from in vitro models to radiation risks in humans.

Update on radiation-based therapies for prostate cancer.

PURPOSE OF REVIEW: This overview summarizes recent developments in radiation-based therapy for prostate cancer. RECENT FINDINGS: Radiation dose escalation continues to be validated as an effective strategy in prostate cancer. Adjuvant radiation therapy became the standard of care after long-term follow-up of the pivotal Southwest Oncology Group 8794 trial demonstrated an overall survival benefit in patients with pT3 disease or positive margin after prostatectomy. Strategies such as hypofractionation and stereotactic body radiation therapy are becoming more common but have yet to be validated in a large trial. New technologies such as Calypso 4D real-time tumor tracking and volumetric-modulated arc therapy promise to potentially increase cure rates and decrease toxicity due to increased accuracy of radiation delivery. SUMMARY: Radiation therapy continues to play a prominent role in the management of prostate cancer. However, new strategies and technologies such as hypofractionation, stereotactic body radiation therapy, volumetric-modulated arc therapy, and Calypso tumor tracking must be prospectively validated.

Patterns of failure among patients with squamous cell carcinoma of the head and neck who obtain a complete response to chemoradiotherapy.

BACKGROUND: The role of adjuvant neck dissection in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who obtain complete clinical and radiologic response following definitive chemoradiation treatment is controversial. METHODS: Patterns of failure among 120 patients with locally advanced SCCHN, all with node-positive disease, treated with concurrent chemoradiation, were analyzed. RESULTS: Ninety-one of the patients achieved a complete response and were observed without undergoing neck dissection. Isolated failure in the neck occurred in 2 patients. The most common site of failure was metastatic disease (17 patients). Six patients had recurrence at the primary only, and 1 experienced failure in the neck and at the primary. Partial responders with resectable disease underwent neck dissection following chemoradiation. This group had worse local control and overall survival compared with complete responders. CONCLUSIONS: We recommend observation after definitive chemoradiation for complete responders. Further research is needed to improve outcomes among partial responders.

Predicting unresectability in pancreatic cancer patients: the additive effects of CT and endoscopic ultrasound.

BACKGROUND: A standardized method for predicting unresectability in pancreatic cancer has not been defined. We propose a system using CT and endoscopic ultrasound (EUS) to assess patients for unresectable pancreatic cancers. METHODS: Radiologic and surgical data from 101 patients who underwent exploration/resection for pancreatic cancer were reviewed. Chi-squares were used to identify five factors significantly correlated with unresectability, which were incorporated into a scoring system (one point for each factor). RESULTS: The resectability rates were 84, 56, and 10% for patients with scores of 0, 1, and 2, respectively. All four patients with three risk factors for unresectability had unresectable tumors. The most accurate results were achieved in patients evaluated with both CT and EUS. DISCUSSION: This scoring system stratifies pancreatic cancer patients into three groups: (1) patients with a score of zero (likely to undergo successful resection), (2) patients with a score of one (likely to benefit from laparoscopic staging prior to attempting resection), and (3) patients with a score of two or higher (low probability of successful resection, who may be better served by neoadjuvant therapy).

An association between preoperative anemia and decreased survival in early-stage non-small-cell lung cancer patients treated with surgery alone.

PURPOSE: Surgical resection is the mainstay of therapy for patients presenting with Stage I and II non-small-cell lung cancer (NSCLC). Despite optimal staging and surgery, these patients are still at significant risk for failure. The purpose of this study is to report a retrospective analysis of the outcome of patients treated with surgery alone, as well as to analyze prognostic factors associated with survival. MATERIALS AND METHODS: From May 2000 to November 2002, there was a total of 125 patients who were treated with surgery for NSCLC at University of Maryland Medical Center. Of these, 82 Stage I and II patients who received surgery alone as the definitive therapy were identified. The median age of the entire cohort was 68 years (range, 43-88 years). There were 48 males and 34 females. Sixty-three patients (76.8%) underwent lobectomies whereas 19 patients (23.2%) underwent nonlobectomy (wedge resection or segmentectomy) procedures. Patients who received neoadjuvant or adjuvant radiation therapy or chemotherapy were excluded from the study. Factors included in univariate and multivariate analyses were age, sex, tumor histology, pathologic stage, p53 status, preoperative hemoglobin (Hgb), and type of surgery performed. Endpoints of the study were relapse-free survival (RFS) and overall survival (OS). RESULTS: Median follow-up was 20.8 months (range, 0.4-43.2 months). For the entire cohort, the 2-year RFS was 66.0% and 2-year OS was 76.3%. Median survival for the entire cohort has not been achieved. In univariate analysis, the only factor that achieved statistical significance was preoperative Hgb level. Patients who had preoperative Hgb <12 mg/dL experienced significantly worse RFS (mean RFS: 26.6 months vs. 34.9 months, p = 0.043) and OS (median OS: 27 months vs. 42.5 months, p = 0.011). For Stage I patients (n = 72), the 2-year RFS and OS were 66.4% and 77.1%, respectively. In the subgroup of stage IA patients (n = 37), there was a trend toward decreased overall survival in the anemic patients (2-year OS of 65.6% vs. 90.9%, p = 0.07). For Stage II patients (n = 10), the 2-year RFS and OS were 60.0% and 66.7%. In the Cox multivariate regression analysis, the only factor that achieved statistical significance was preoperative Hgb, with patients with Hgb <12 mg/dL having decreased RFS (RR 4.1, p = 0.020) and OS (RR 2.9, p = 0.026). There was a trend toward worse RFS (p = 0.056) and OS (p = 0.068) in p53-negative patients (n = 39). Stage, histologic type, type of surgery performed, age, and sex did not affect outcome. CONCLUSIONS: In our cohort of mostly Stage I NSCLC patients treated with surgery only, preoperative Hgb <12 mg/dL predicted for worse outcome. This effect was observed even in the traditionally low-risk subgroup of completely resected stage IA patients. Much has been written in the literature about anemia causing possible worsening of tumor hypoxia within solid tumors, thereby increasing radio-resistance. This has been a popular argument to explain poorer outcomes of anemic patients with solid tumors who undergo radiotherapy. However, our data suggest that anemia may be a sign of a more aggressive tumor that is at an increased risk of failure independent of the treatment modality.

Factors predicting local tumor control after gamma knife stereotactic radiosurgery for benign intracranial meningiomas.

PURPOSE: To determine the long-term outcomes and prognostic factors in benign intracranial meningiomas treated with gamma knife stereotactic radiosurgery (GK-SRS). METHODS AND MATERIALS: Between 1992 and 2000, 162 patients with benign meningiomas were treated with GK-SRS at the University of Maryland Medical Center. Complete follow-up was available in 137 patients. All patients underwent magnetic resonance imaging (MRI)-based treatment planning. Serial MRIs and clinical exams were performed to assess tumor response. GK-SRS was the primary treatment in 85 patients (62%), whereas 52 patients (48%) had prior surgical resections. The median prescribed dose was 14 Gy (range, 4-25 Gy) to the 50% isodose line. The median tumor volume, treatment volume, and conformity index were 4.5 cc (range, 0.32-80.0 cc), 6.3 cc (range, 1.0-75.2 cc), and 1.34 (range, 0.65-3.16), respectively. The median follow-up for the entire cohort was 4.5 years (range, 0.33-10.5 years). The following factors were included in the statistical analysis for disease-free survival (DFS) and overall survival (OS): sex, age, dose, gross tumor volume (GTV), conformity index (CI), and dural tail coverage. RESULTS: Serial MRI analysis was available in 121 patients (88.3%). Decrease in tumor size was observed in 34 patients (28.1%), whereas there was no change in 77 patients (63.6%), for a crude radiographic control rate of 91.7%. Increase in tumor size was seen in 10 patients (8.3%). New neurologic deficits attributed to the treatment developed in 10 patients (8.3%). The mean DFS and OS for the entire cohort are 4.6 years and 5.0 years, respectively. The 5-year actuarial DFS and OS were 86.2% and 91.0%, respectively. Univariate analysis revealed GTV, sex, CI, and dural tail treatment to be significant prognostic factors. Patients with GTV < or =10 cc also had longer survivals, with the 5-years DFS and OS of 91.9% vs. 68.0% (p = 0.038) and 100% vs. 59.7% (p = 0.0001), respectively. The 5-years actuarial DFS and OS for females vs. males were 90.2% vs. 74.2% (p = 0.0094) and 91.6% vs. 89.1% (p = 0.016), respectively. Patients with CI > or =1.4 achieved a longer DFS, with a 5-year DFS of 95.2% vs. 77.3% (p = 0.01). Patients who had the dural tail treated also had higher 5-year DFS (96.0% vs. 77.9%, p = 0.038). Patients with lower conformity (i.e., CI > or =1.4) tended to have the dural tail covered in the prescription isodose line (p = 0.04). The only factor significant in the multivariate analysis was for patients with GTV >10 cc, who had a worse DFS (hazard ratio 4.58, p = 0.05). CONCLUSIONS: This report adds to the literature that supports the efficacy and safety of GK-SRS in the management of patients with benign intracranial meningiomas. Our report identified male patients, patients with a CI <1.4, and tumor size greater than 10 cc to have a worse prognosis. Patients who were treated with less conformal plans to cover the dural tail had better outcomes. Our data clearly demonstrate the need to adequately cover the dural tail in patients treated with GK-SRS for benign intracranial meningiomas.