Rupa Parvataneni

Phase II Study of Erlotinib Plus Temozolomide During and After Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

PURPOSEnThis open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response.nnnPATIENTS AND METHODSnSixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials.nnnRESULTSnMedian survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival.nnnCONCLUSIONnPatients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.

Magnetic Resonance of 2-Hydroxyglutarate in IDH1-Mutated Low-Grade Gliomas

2-Hydroxyglutarate can be detected ex vivo in biopsy tissue from IDH1-mutant low-grade gliomas with proton high-resolution magic angle spinning NMR spectroscopy. Gliomas Make the Grade Tumors of the central nervous systems can be classified, or “graded,” on a scale of I to IV, according to their capacity to proliferate and invade surrounding tissue (with I being benign). Although determining the grade of brain tumor malignancy is important for doctors to predict survival and prescribe treatment, it cannot sufficiently explain the variation in clinical outcome. Some have attempted to classify brain tumors on the basis of acquired mutations, which has provided further insight into the characteristic diversity observed in survival. For example, one mutation in the gene isocitrate dehydrogenase (IDH) has demonstrated prolonged life expectancy for patients with low-grade brain tumors. Now, Elkhaled, Jalbert, and colleagues have shown that accumulation of a metabolite resulting from this mutation can be detected using magnetic resonance imaging techniques. Under normal conditions, the IDH enzyme converts the metabolite isocitrate to α-ketoglutarate. When IDH is mutated, its enzyme product further converts α-ketoglutarate to an otherwise scarce metabolite, 2-hydroxyglutarate (2HG). Because improved patient outcome has been associated with IDH mutations, the accumulation of 2HG might therefore be able to predict favorable genotypes. Elkhaled, Jalbert, and colleagues used an imaging method based on proton high-resolution magic angle spinning (1H HR-MAS) nuclear magnetic resonance (NMR) spectroscopy to determine whether the presence of 2HG was detectable. A total of 104 tissue (biopsy) samples from 52 patients with recurrent grade II gliomas (some of which had converted to grades III or IV) were evaluated for the presence of 2HG and the IDH1 mutation. 2HG proved to be detectable by spectroscopic analysis and showed approximately 86% concordance with the status of IDH1 mutation, as determined by antibody staining and genetic sequencing. Furthermore, 2HG abundance was shown to be similar across all brain tumor grades when normalized by cellularity, suggesting that its relative production per cell remains the same even after lesions have converted to higher histologic grades. This finding bears considerable significance for clinical evaluation of the malignancy grade and extent of tumor lesions. Finally, 2HG levels were determined to negatively correlate with normal vascularity. Given the current hypotheses in the literature regarding the influence of 2HG on vascular endothelial growth factor (VEGF), this result may be of interest for designing anti-angiogenic strategies for treating tumors with IDH mutations. This ex vivo study—along with its in vivo companion by Andronesi et al.—shows that the use of magnetic resonance imaging technology, already routine in the clinic, could significantly improve the management of brain tumors. Recent studies have indicated that a significant survival advantage is conferred to patients with gliomas whose lesions harbor mutations in the genes isocitrate dehydrogenase 1 and 2 (IDH1/2). IDH1/2 mutations result in aberrant enzymatic production of the potential oncometabolite d-2-hydroxyglutarate (2HG). Here, we report on the ex vivo detection of 2HG in IDH1-mutated tissue samples from patients with recurrent low-grade gliomas using the nuclear magnetic resonance technique of proton high-resolution magic angle spinning spectroscopy. Relative 2HG levels from pathologically confirmed mutant IDH1 tissues correlated with levels of other ex vivo metabolites and histopathology parameters associated with increases in mitotic activity, relative tumor content, and cellularity. Ex vivo spectroscopic measurements of choline-containing species and in vivo magnetic resonance measurements of diffusion parameters were also correlated with 2HG levels. These data provide extensive characterization of mutant IDH1 lesions while confirming the potential diagnostic value of 2HG as a surrogate marker of patient survival. Such information may augment the ability of clinicians to monitor therapeutic response and provide criteria for stratifying patients to specific treatment regimens.

Regional variation in histopathologic features of tumor specimens from treatment-naive glioblastoma correlates with anatomic and physiologic MR Imaging

Histopathologic evaluation of glioblastoma multiforme (GBM) at initial diagnosis is typically performed on tissue obtained from regions of contrast enhancement (CE) as depicted on gadolinium-enhanced, T1-weighted images. The non-enhancing (NE) portion of the lesion, which contains both reactive edema and infiltrative tumor, is only partially removed due to concerns about damaging functioning brain. The purpose of this study was to evaluate histopathologic and physiologic MRI features of image-guided tissue specimens from CE and NE regions to investigate correlations between imaging and histopathologic parameters. One hundred nineteen tissue specimens (93 CE and 26 NE regions) were acquired from 51 patients with newly diagnosed GBM by utilizing stereotactic image-guided sampling. Variables of anatomic, diffusion-weighted imaging (DWI), and dynamic susceptibility-weighted, contrast-enhanced perfusion imaging (DSC) from each tissue sample location were obtained and compared with histopathologic features such as tumor score, cell density, proliferation, architectural disruption, hypoxia, and microvascular hyperplasia. Tissue samples from CE regions had increased tumor score, cellular density, proliferation, and architectural disruption compared with NE regions. DSC variables such as relative cerebral blood volume, peak height, and recovery factor were significantly higher, and the percentage of signal intensity recovery was significantly lower in the CE compared with the NE regions. DWI variables were correlated with histopathologic features of GBM within NE regions. Image-guided tissue acquisition and assessment of residual tumor from treatment-naive GBM should be guided by DSC in CE regions and by DWI in NE regions.

Tumor Recurrence 5 Years after Treatment of Cutaneous Basal Cell Carcinoma and Squamous Cell Carcinoma

For most cutaneous basal cell and squamous cell carcinomas (nonmelanoma skin cancers [NMSC]) data are insufficient to permit evidence-based choices among treatments. To compare tumor recurrence after treatments, we conducted a prospective cohort study of consecutive patients with primary NMSC treated with the most common treatments in two practices in 1999–2000. Recurrence was determined from medical records by observers blinded to treatment type. 24.3% of tumors (N=361) were treated with destruction with electrodessication / curettage, 38.3% (N=571) with excision, and 37.4% (N=556) with histologically-guided serial excision (Mohs surgery). Follow-up was available for 1174 patients with 1488 tumors (93.8%) at median 7.4 years; overall 5-year tumor recurrence rate [95% Confidence Interval] was 3.3% [2.3, 4.4]. Unadjusted recurrence rates did not differ after treatments: 4.9% [2.3, 7.4] after destruction, 3.5% [1.8, 5.2] after excision, and 2.1% [0.6, 3.5] after Mohs surgery (P=0.26), and no difference was seen after adjustment for risk factors. In tumors treated only with excision or Mohs surgery, the hazard of recurrence was not significantly different, even after adjustment for propensity for treatment with Mohs surgery. These data indicate that common treatments for NMSC were at least 95% effective, and further studies are needed to guide therapeutic choices for different clinical subgroups.

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Survival analysis in patients with newly diagnosed glioblastoma using pre- and postradiotherapy MR spectroscopic imaging

BACKGROUNDnThe objective of this study was to examine the predictive value of parameters of 3D (1)H magnetic resonance spectroscopic imaging (MRSI) prior to treatment with radiation/chemotherapy (baseline) and at a postradiation 2-month follow-up (F2mo) in relationship to 6-month progression-free survival (PFS6) and overall survival (OS).nnnMETHODSnSixty-four patients with newly diagnosed glioblastoma multiforme (GBM) being treated with radiation and concurrent chemotherapy were involved in this study. Evaluated were metabolite indices and metabolite ratios. Logistic linear regression and Cox proportional hazards models were utilized to evaluate PFS6 and OS, respectively. These analyses were adjusted by age and MR scanner field strength (1.5 T or 3 T). Stepwise regression was performed to determine a subset of the most relevant variables.nnnRESULTSnAssociated with shorter PFS6 were a decrease in the ratio of N-acetyl aspartate to choline-containing compounds (NAA/Cho) in the region with a Cho-to-NAA index (CNI) >3 at baseline and an increase of the CNI within elevated CNI regions (>2) at F2mo. Patients with higher normalized lipid and lactate at either time point had significantly worse OS. Patients who had larger volumes with abnormal CNI at F2mo had worse PFS6 and OS.nnnCONCLUSIONSnOur study found more 3D MRSI parameters that predicted PFS6 and OS for patients with GBM than did anatomic, diffusion, or perfusion imaging, which were previously evaluated in the same population of patients.

Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: A phase I study†

We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCbeta] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status > or =60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m(2) daily) followed by adjuvant temozolomide (200 mg/m(2)) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if < or =1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009.

Treatment of Nonfatal Conditions at the End of Life: Nonmelanoma Skin Cancer

IMPORTANCEnNonmelanoma skin cancer (NMSC) is the most common cancer and predominantly affects older patients. Because NMSCs do not typically affect survival or short-term quality of life, the decision about whether and how to treat patients with limited life expectancy (LLE) is challenging, especially for asymptomatic tumors.nnnOBJECTIVEnTo compare treatment patterns and clinical outcomes of patients with NMSC with and without LLE.nnnDESIGN, SETTING, AND PARTICIPANTSnA prospective cohort study of 1536 consecutive patients diagnosed with NMSC at 2 dermatology clinics: a university-based private practice and a Veterans Affairs Medical Center in San Francisco, California. Patients were recruited in 1999 through 2000 and followed up for a median of 9 years. A total of 1360 patients with 1739 tumors (90%) were included in the final analysis. Limited life expectancy was defined as patients either 85 years or older at the time of diagnosis or patients with multiple comorbidities (Charlson Comorbidity Index of ≥ 3). Treatment options included no treatment, destruction, or 2 types of surgery-elliptical excision or Mohs surgery.nnnMAIN OUTCOMES AND MEASURESnTreatment type.nnnRESULTSnMost NMSCs (69%) were treated surgically, regardless of patient life expectancy. The choice of surgery was not influenced by patient prognosis in univariate or multivariable models adjusted for tumor and patient characteristics. Many patients with LLE (43%) died within 5 years, none of NMSC. Tumor recurrence was rare (3.7% at 5 years [95% CI, 2.6%-4.7%]) in all patients. Although serious complications were unusual, approximately 20% of patients with LLE reported complications of therapy, compared with 15% of other patients.nnnCONCLUSIONS AND RELEVANCEnMost NMSCs are treated surgically, regardless of the patients life expectancy. Given the very low tumor recurrence rates and high mortality from causes unrelated to NMSC in patients with LLE, clinicians should consider whether these patients would prefer less invasive treatment strategies.

Identifying the needs of brain tumor patients and their caregivers

The purpose of this study is to identify the needs of brain tumor patients and their caregivers to provide improved health services to these populations. Two different questionnaires were designed for patients and caregivers. Both questionnaires contained questions pertaining to three realms: disease symptoms/treatment, health care provider, daily living/finances. The caregivers’ questionnaires contained an additional domain on emotional needs. Each question was evaluated for the degree of importance and satisfaction. Exploratory analyses determined whether baseline characteristics affect responder importance or satisfaction. Also, areas of high agreement/disagreement in satisfaction between the participating patient-caregiver pairs were identified. Questions for whichxa0>50% of the patients and caregivers thought were “very important” butxa0>30% were dissatisfied include: understanding the cause of brain tumors, dealing with patients’ lower energy, identifying healthful foods and activities for patients, telephone access to health care providers, information on medical insurance coverage, and support from their employer. In the emotional realm, caregivers identified 9 out of 10 items as important but need further improvement. Areas of high disagreement in satisfaction between participating patient-caregiver pairs include: getting help with household chores (P valuexa0=xa00.006) and finding time for personal needs (P valuexa0<xa00.001). This study provides insights into areas to improve services for brain tumor patients and their caregivers. The caregivers’ highest amount of burden is placed on their emotional needs, emphasizing the importance of providing appropriate medical and psychosocial support for caregivers to cope with emotional difficulties they face during the patients’ treatment process.

Timing of Subsequent New Tumors in Patients Who Present With Basal Cell Carcinoma or Cutaneous Squamous Cell Carcinoma

IMPORTANCEnPatients with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) (often termed nonmelanoma skin cancer or keratinocyte carcinoma [KC]) often develop new KCs, but information is limited on the frequency and timing of these subsequent tumors. This information is crucial to guide follow-up care.nnnOBJECTIVEnTo determine the timing of subsequent new KCs in patients who present with KC.nnnDESIGN, SETTING, AND PARTICIPANTSnWe enrolled a consecutive cohort of 1426 patients diagnosed as having biopsy-proven KC from January 1, 1999, through December 31, 2000, in a university dermatology practice and its affiliated Department of Veterans Affairs dermatology service. After exclusion of patients with basal cell nevus syndrome and immunocompromise, 1284 patients (90.0%) were followed up prospectively for a mean of 5.7 (range, 0-12.3) years.nnnMAIN OUTCOMES AND MEASURESnWe assessed the risks for subsequent KCs over time using single-failure and multiple-failure models. We separately assessed outcomes after first lifetime KCs and after nonfirst lifetime KCs. We also performed secondary analyses of the risk for a subsequent BCC after a prior BCC diagnosis and the risk for a subsequent SCC after a prior SCC diagnosis.nnnRESULTSnThe risk for a subsequent KC was substantially lower after the first lifetime KC diagnosis: 14.5% (95% CI, 11.9%-17.7%) at 1 year, 31.1% (95% CI, 27.3%-35.3%) at 3 years, and 40.7% (95% CI, 36.5%-45.2%) at 5 years, than after a nonfirst KC: 43.9% (95% CI, 42.0%-45.9%) at 1 year, 71.1% (95% CI, 69.1%-73.0%) at 3 years, and 82.0% (95% CI, 80.2%-83.7%) at 5 years. Secondary analyses of the risks for a subsequent BCC after a prior BCC diagnosis and of a subsequent SCC after a prior SCC diagnosis yielded results consistent with the analyses for the pooled KC sample.nnnCONCLUSIONS AND RELEVANCEnAlthough all patients with KC are assumed to be at high risk for subsequent tumors, a subset may not develop another KC after their first tumor. Whether these findings are related to biological or behavioral differences or to differences in health care services should be investigated further to inform and improve care. Ongoing routine screening for subsequent KC may not be indicated for all patients with KC. Skin cancer screening can be improved with a better understanding of the course and frequency of subsequent KC diagnoses.