Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas

Protracted low dose temozolomide (75 mg/m²/day on days 1–21 of 28 days) offers potential advantages over standard temozolomide schedules (200 mg/m²/day on days 1–5 of 28 days) including greater cumulative drug exposure and depletion of O⁶-alkylguanine DNA alkyltransferase levels, theoretically overcoming intrinsic chemoresistance. We retrospectively review our experience in 25 patients with pathologically proven low grade gliomas (LGG) treated with protracted low dose temozolomide to primarily quantify its toxicity and secondarily to assess efficacy. None had previously received radiation. Tumor response was graded based on changes in tumor size, steroid requirements, and clinical exam. About 243 cycles of protracted low dose temozolomide were administered. Three patients (12%) were changed to standard temozolomide dosing due to side effects, including intractable nausea (n = 2) and multiple cytopenias (n = 1). The most frequent toxicities were fatigue (76%), lymphopenia (72% [48% high grade]), constipation (56%), and nausea (52%). High grade toxicities (other than lymphopenia) included secondary malignancy, pruritis, hyponatremia, neutropenia, leukopenia, and cognitive decline (n = 1 for each). Tumor response rate was 52% and and disease control rate was 84%. Six month PFS was 92% and 12 month PFS was 72%. Response rates and PFS were independent of pathological subtype, deletion status, and indication for chemotherapy. Protracted low dose temozolomide has a distinct spectrum of toxicities compared to standard dosing but is well tolerated in most patients and may provide improved response rates compared to standard dosing. The results of larger randomized trials are needed to assess its potential advantages over other management schemes.     

Longitudinal cognitive follow-up in low grade gliomas

Background In patients with low-grade glioma (LGG), the tumor and its treatment with conformal radiation therapy (RT) and chemotherapy can disrupt cognitive function. However, the contribution of disease and treatment to long-term cognitive outcome remains to be elucidated. In this study, we performed longitudinal cognitive follow-up in a subgroup of patients who received RT, chemotherapy, or no treatment. Methods Twenty-five LGG patients underwent neuropsychological evaluations at study entry, and 6 and 12 months subsequently; 9 patients had RT ± chemotherapy prior to enrollment and 16 had no treatment. Results At the initial evaluation, treated patients had impaired performance on motor speed only, but scored 1 standard deviation below normative values on tests of executive functions; untreated patients had no cognitive impairment. Repeated measures analyses of variance showed a significant variation over time (P = 0.03) in nonverbal memory (delayed recall); treated patients’ performance improved at the 6-month follow-up to a level comparable to untreated patients, but both groups declined slightly by the 12-month evaluation. In a subset of patients (N = 16) available for an additional cognitive evaluation, significant changes between the 12-month and the long-term follow-up were seen in phonemic verbal fluency, mood and quality of life; untreated patients seen at short intervals improved slightly while treated patients seen at longer intervals declined. Conclusions Longitudinal follow-up showed that both disease duration and treatment with RT ± chemotherapy contributed to a mild decrement in nonverbal recall and in some aspects of executive functions and quality of life in this group of LGG patients. Presented in part at the 8th World Congress of Psycho-Oncology, October 2006.     

Nitrosourea-based chemotherapy for low grade gliomas failing initial treatment with temozolomide

There is a growing evidence of using Temozolomide as upfront therapy for progressive low grade gliomas. No data exist on the efficacy of nitrosoureas as an alternative to radiotherapy in those patients who progress after Temozolomide. We retrospectively reviewed 30 patients with median age of 46 years. Twenty-one patients had pure oligodendrogliomas. Thirteen patients had a non-enhancing tumor at progression after Temozolomide. The chromosomes 1p/19q were co-deleted in 5 cases and retained in 10 cases. Response rate was 10% (3 minor responses achieved in non-enhancing tumors). Tolerance was acceptable (17% grade III and IV myelosupression). Median PFS was 6.5 months. Median OS from start of salvage treatment was 23.4 months. Tumors without contrast enhancement demonstrated a better prognosis than those with contrast enhancement both in term of PFS (P = 0.0003) and OS (P = 0.0006). Chromosomes 1p/19q codeletion was not predictive for objective response to salvage treatment but correlated with a better PFS (P = 0.02). In conclusion, salvage NU chemotherapy provide disappointing results in TMZ-pretreated low grade gliomas (LGG), which should be treated in priority by conventional radiotherapy especially in LGG that display contrast enhancement at progression.     

Mutation in the PTEN/MMAC1 gene in archival low grade and high grade gliomas

The PTEN gene, located on 10q23.3, has recently been described as a candidate tumour suppressor gene that may be important in the development of advanced cancers, including gliomas. We have investigated mutation in the PTEN gene by direct sequence analysis of PCR products amplified from samples microdissected from 19 low grade (WHO Grade I and II) and 27 high grade (WHO grade III and IV) archival, formalin-fixed, paraffin-embedded gliomas. Eleven genetic variants in ten tumours have been identified. Eight of these are DNA sequence changes that could affect the encoded protein and were present in 0/2 pilocytic astrocytomas, 0/2 oligoastrocytomas, 0/1 oligodendroglioma, 0/14 astrocytomas, 3/13 (23%) anaplastic astrocytomas and 5/14 (36%) glioblastomas. PTEN mutations were found exclusively in high grade gliomas; this finding was statistically significant. Only two of the PTEN genetic variants have been reported in other studies; two of the genetic changes are in codons in which mutations have not been found previously. The results of this study indicate that mutation in the PTEN gene is present only in histologically more aggressive gliomas, may be associated with the transition from low histological grade to anaplasia, but is absent from the majority of high grade gliomas.     

Radiotherapy for high grade gliomas

This presentation will review recent data on the treatment of high grade gliomas. It deals primarily with results of radiotherapy even though several of the clinical trials to be considered also included chemotherapy. Present emphasis will be on, but not limited to, the larger prospective randomized trials conducted by various cooperative clinical groups in the United States, the United Kingdom and on the continent.     

Low grade gliomas treated with adjuvant radiation therapy in the modern imaging era

The purpose of this study is to evaluate tumor control and failure patterns in patients with low grade gliomas treated with surgery and conventional adjuvant radiation therapy. Twenty-eight patients with low grade gliomas (7 grade I, 21 grade II) were retrospectively evaluated. Extent of resection was gross total (3), subtotal (17), and biopsy alone (8). All grade I tumors underwent subtotal resection. Median radiation therapy dose was 54 Gy delivered to localized fields. Tumor control and patterns of failure were determined from follow-up computed tomography and/or magnetic resonance scans. Median follow-up was 86 months (range, 2.4-177 months). Thirteen patients (46%) (four grade I, nine grade II) developed tumor progression. The 5-year actuarial progression-free survival rates for grade I and grade II patients were 86% and 51%, respectively. Corresponding 5-year actuarial survival rates were 100% and 70%. All recurrences were within the treated volume. Our results reveal that conventional adjuvant radiation therapy is associated with high rates of local tumor progression in both grade II and incompletely resected grade I low grade gliomas. Alternative strategies need to be explored in these patients in an effort to improve tumor control and outcome.     

Trends in gastric cancer sex ratio in the United States

Recent reports have suggested that the male/female ratio for gastric cancer has decreased over time and that the mean age of cases has increased. The authors calculated age- and sex-specific mortality rates for gastric cancer from 1950 through 1979 for whites using data from US Vital Statistics and population estimates from the US Census Bureau. Whereas sex ratios based on crude mortality rates showed a decrease over time from 1.7 in 1950 to 1.5 in 1979, similar ratios based on age-adjusted mortality rates showed an increase from 1.8 to 2.1. An increase in mean age at death over time was consistent with the increase in age of the population. The authors conclude that factors responsible for the decrease in gastric cancer mortality in the United States appear to have affected males and females equally. The overall data do not support the emergence of a new form of gastric cancer with a sex ratio or age pattern different from that found in the past.     

Trends in the use of cytoreductive nephrectomy in the United States

BackgroundTwo randomized trials published in 2001 established CyNx for patients with metastatic renal carcinoma (mRCC) as a treatment standard in the cytokine era. However, first-line systemic therapy for mRCC changed in 2005 with FDA approval of VEGFR TKIs. We evaluated the patterns of use of CyNx from 2000 to 2008.Materials and MethodsThe National Cancer Database was queried for patients diagnosed with mRCC. Patients who underwent CyNx were identified and were further categorized by pre-VEGFR versus VEGFR TKI era, race, insurance status, and hospital. For these subcategories, prevalence ratios (PRs) were generated using the proportion of patients with mRCC undergoing CyNx versus those not undergoing CyNx.ResultsOf the 47,417 patients (pts) identified with mRCC, the prevalence of cytoreductive nephrectomy increased 3% each year from 2000 to 2005 (P < .0001), then decreased 3% each year from 2005 to 2008 (P = .0048), with a significant difference between the eras (0.97 vs. 1.025; P < .0001). Black and Hispanic pts were less likely than Caucasian pts to undergo CyNx. Pts with Medicaid, Medicare, and no insurance were less likely than pts with private insurance to undergo CyNx. Pts diagnosed at community hospitals were significantly less likely than pts at teaching hospitals to undergo CyNx.ConclusionThe use of CyNx has declined in the VEGFR-TKI era. In addition, racial and socioeconomic disparities exist in the use of CyNx. The results of pending randomized trials evaluating the role of CyNx in the VEGFR-TKI era are awaited to optimize use of this modality and address potential disparities.     

Trends in renal tumor surgery delivery within the United States

BACKGROUND:

Most small renal tumors are amenable to partial nephrectomy (PN). Studies have documented the association of radical nephrectomy (RN) with an increased risk of comorbid conditions, such as chronic kidney disease. Despite evidence of equivalent oncologic outcomes, PN remains under used within the United States. In this study, the authors identified the most recent trends in kidney surgery for small renal tumors and determined which factors were associated with the use of PN versus RN within the United States.

METHODS:

A population‐based patient cohort was analyzed using the Surveillance, Epidemiology and End Results cancer registry (SEER 1999‐2006). The authors identified 18,330 patients ages 40 to 90 years who underwent surgery for kidney tumors ≤4 cm in the United States between 1999 and 2006.

RESULTS:

In total, 11,870 patients (65%) underwent RN, and 6460 patients (35%) underwent PN. The ratio of PN to RN increased yearly (P < .001), representing 45% of kidney surgeries in 2006 for small tumors. There were significant differences in the cohort of patients who underwent PN versus RN, including age, sex, tumor location, marital status, year of treatment, and tumor size. When adjusting for these variables, being a man, age ≤70 years, urban residence, smaller tumor size, and more recent treatment year were predictors of PN.

CONCLUSIONS:

Although the total numbers of PN procedures increased in the United States between 1999 and 2006, there remains a significant under use of PN, particularly among women, the elderly, and those living in rural locations. Further investigation will be required to determine the reasons for these disparities, and strategies to optimize access to PN need to be developed. Cancer 2010. © 2010 American Cancer Society.     

Gastric Cancer Treatments and Survival Trends in the United States

Gastric cancer is the third most common cause of cancer deaths worldwide. Despite evidence-based recommendation for treatment, the current treatment patterns for all stages of gastric cancer remain largely unexplored. This study investigates trends in the treatments and survival of gastric cancer. The National Cancer Database was used to identify gastric adenocarcinoma patients from 2004–2016. Chi-square tests were used to examine subgroup differences between disease stages: Stage I, II/III and IV. Multivariate analyses identified factors associated with the receipt of guideline concordant care. The Kaplan–Meier method was used to assess three-year overall survival. The final cohort included 108,150 patients: 23,584 Stage I, 40,216 Stage II/III, and 44,350 Stage IV. Stage specific guideline concordant care was received in only 73% of patients with Stage I disease and 51% of patients with Stage II/III disease. Patients who received guideline consistent care had significantly improved survival compared to those who did not. Overall, we found only moderate improvement in guideline adherence and three-year overall survival during the 13-year study time period. This study showed underutilization of stage specific guideline concordant care for stage I and II/III disease.     

Fast neutron beam radiation therapy in the United States

Following a 30-year hiatus after Dr. Stone's work in the 1930's and 1940's, clinical trials with fast neutrons were restarted in the United States in 1972. Approximately 2500 patients have been treated with neutrons since that time. Three hundred and seven patients with squamous cell carcinomas of the head and neck were entered on an RTOG-coordinated randomized study comparing standard photon irradiation with mixed beam radiation therapy. No significant differences were noted in the local control, survival or complication rates. One hundred and sixty patients were entered on a randomized glioblastoma study. Although there were no significant differences in median survival, autopsy results showed greater tumor effect on the neutron-treated tumors. Twenty-six patients were treated for transitional cell carcinomas of the bladder with either preoperative mixed beam irradiation or mixed beam irradiation alone. Both the local control rates and survival rates compare favorably with photon radiation therapy. The future of fast neutron beam radiation therapy in the United States is discussed.     

Clinical utility of cerebrovascular reactivity mapping in patients with low grade gliomas

AIM: To evaluate neurovascular uncoupling (NVU) associated with low grade gliomas (LGG) using blood oxygen level dependent (BOLD) cerebrovascular reactivity mapping.METHODS: Seven patients with low grade gliomas referred by neurosurgeons for presurgical mapping were included in this pilot study. Cerebrovascular reactivity (CVR) mapping was performed by acquiring BOLD images while patients performed a block-design breath-hold (BH) hypercapnia task. CVR mapping was expressed as BOLD percentage signal change (PSC) from baseline associated with performance of the BH hypercapnia task. Standard T2* Dynamic Susceptibility Contrast perfusion imaging was performed and relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) maps were generated. Structural T1 weighted MR images were also acquired. A correlation analysis between intratumoral normalized (via ratio with contralateral homologous regions) BOLD BH PSC [referred to as (n_CVR)] and intratumoral normalized resting state rCBV (rCBF) values (i.e., n_CBV and n_CBF, respectively) was performed.RESULTS: No significant correlation was seen between the normalized BOLD BH PSC (i.e., n_CBV) and n_CBV or n_CBF. However, the average n_CVR (median = 0.50, z = -2.28, P = 0.01) was significantly less than 1.0, indicating abnormally reduced vascular responses in the tumor regions relative to normal contralesional homologous regions, whereas the average n_CBV (median = 0.94, z = -0.92, P = 0.375) and n_CBF (median = 0.93, z = -1.16, P = 0.25) were not significantly higher or lower than 1.0, indicating iso-perfusion in the tumor regions relative to normal contralesional homologous regions. These findings suggest that in LGG, hyperperfusion that is seen in high grade gliomas is not present, but, nevertheless, abnormally decreased regional CVR is present within and adjacent to LGG. Since the patients all demonstrated at least some residual function attributable to the cortical regions of impaired CVR, but were incapable of producing a BOLD response in these regions regardless of the tasks performed, such regionally decreased CVR is indicative of NVU. The low n_CVR ratios indicate high prevalence of NVU in this LGG cohort, which is an important consideration in the interpretation of clinical presurgical mapping with functional magnetic resonance (MR) imaging.CONCLUSION: Our preliminary study shows that BH CVR mapping is clinically feasible and demonstrates an unexpectedly high prevalence of NVU in patients with LGG.     

Trends in treatments for prostate cancer in the United States, 2010-2015

Although annual mortality trends for prostate cancer were stabilized in recent years, understanding the exact treatment changes is necessary for optimal management. Utilization of not-otherwise specified (NOS) treatments for prostate cancer was unclear. Thus, this study aimed to analyze trends in treatment for prostate cancer in the U.S. from 2010 to 2015 and examine whether the treatment for the prostate cancer in the U.S. is compliant with clinical practice guidelines. Using joinpoint regression models, we examined trends in the rate and proportion of age-standardized utilization (ASUR and ASUP) of treatments for prostate cancer diagnosed during 2010-2015 in the U.S. based on the data from the Surveillance, Epidemiology, and End Results (SEER, 2018 data-release, with linkage to active surveillance/watchful waiting [AS/WW]) cancer registry program. Among 316,690 men with prostate cancer diagnosed during 2010-2015, ASUR and ASUP for radical prostatectomy, radiotherapy, AS/WW and NOS treatment were 32.7, 34.4, 10.0 and 40.1 per 100,000, and 27.9%, 29.3%, 8.5% and 34.2%, respectively. Trends in the overall ASUR for prostate cancer treatments differed by cancer risk group, patients’ age, race/ethnicity, Gleason score, insurance status, and the average education level, average poverty-level and foreign-born person percentage of the patient’s residence-county, but not by rural-urban continuum or region. ASUP of radical prostatectomy decreased from 9.8% in 2010 to 4.8% in 2015 (annual percent change [APC] = -12.0%, 95% CI, -15.9 to -7.9%), and the decrease was observed in all different risk groups. ASUP of AS/WW increased from 16.4% in 2010 to 30.2% in 2013 (APC = 22.7%, 95% CI, 4.6 to 44.0%) and then remained stable through 2013 to 2015 (APC = 1.9%, 95% CI, -24.1 to 36.9%). The increasing tendency of AS/WW only occurred in the low-risk and intermediate-risk groups. The ASUP of NOS treatment has increased from 32.3% in 2010 to 36.8% in 2015 (P<0.01). In conclusion, ASUR and ASUP for prostate cancer treatments, including NOS treatment, had changed during 2010-2015. Their trends appeared to differ by cancer risk-group, age, race/ethnicity, Gleason score and socioeconomic factors. Future studies are warranted to understand the impacts of upward trends in ASUP of NOS treatments and AS/WW on patient survival and prostate cancer mortality.     

High dose radiation therapy in the treatment of malignant gliomas: final report.

One hundred patients with supratentorial malignant gliomas were prescribed to receive postoperative whole brain irradiation with doses ≥5000 rad; 41 had astrocytoma grade III and 59 had grade IV tumors. The median survival was 91 weeks for patients with grade III tumors and only 42 weeks for those with grade IV (p < 0.01). For both grades, patients who were ≤45 years of age survived significantly better than patients who were older at diagnosis (p < 0.05). Patients with tumors at each grade were divided into three groups depending on the total dose delivered to the tumor; 5000, 6000, 7500 rad (median doses).For patients with grade IV tumors the median survival was 30, 42 and 56 weeks respectively, these differences were significant (p < 0.05) between the extremes but not between consecutive dose groups and were maintained only up to 2 years from the initiation of treatment. For patients with grade III tumors, the median survival was 43, 82 and 204 weeks respectively; these differences were significant (p < 0.05) between consecutive dose groups and between extremes and were maintained up to 4 years from the initiation of treatment. For 22 patients with grade IV who were treated with high-doses (7500 rad), the median time for recurrence was 43 weeks while for six patients with grade III tumors it was 158 weeks.The use of higher radiation doses was well tolerated; it did not compromise the quality of survival, and did not yield normal brain tissue necrosis. However, these doses did not seem to alter the total survival of patients, nor did they seem capable of sterilizing these tumors. Histopathological changes that were observed in normal brain tissue that was irradiated with 7000–8000 rad suggest that increasing total doses beyond this range might attain tumor sterilization, but could also lead to frank radiation necrosis in these patients.     

The role of up-front radiation therapy for incompletely resected pediatric WHO grade II low-grade gliomas

The purpose of this study was to assess the impact of early radiation therapy and extent of surgical resection on progression-free survival (PFS) and overall survival (OS) in children with WHO grade II low-grade gliomas (LGGs). We conducted a historical cohort study of 90 patients, ages 21 or younger, diagnosed with WHO grade II LGGs between 1970 and 1995. Median follow-up for surviving patients was 9.4 years (range, 0.5-22.6 years). Tests for variables correlating with OS and PFS were conducted by using log-rank tests and Cox proportional hazards models. Eleven patients underwent gross total resections (GTRs), 43 had subtotal resections, and 34 underwent biopsy only at diagnosis. Two patients underwent biopsy at time of recurrence. Of the 90 patients, 52 received radiation as part of their initial therapy following diagnosis (early-RT group). The overall five-year PFS and OS rates +/- SE were 56% +/- 5% and 90% +/- 3%, respectively. Ten-year PFS and OS rates were 42% +/- 6% and 81% +/- 5%, respectively. For patients older than three years and without GTRs, administration of early radiation did not appear to influence PFS or OS (P = 0.98 and P = 0.40, respectively; log-rank test). This was confirmed by multivariate analyses (P = 0.95 and P = 0.33 for PFS and OS, respectively). Of the 11 patients with GTRs, disease progressed in only two, and all were alive with no evidence of disease at last follow-up. Patients who underwent GTRs had significantly longer PFS (P = 0.02), but did not have significantly improved OS. Excellent long-term survival rates were achieved for children with WHO grade II LGGs. We were unable to demonstrate a benefit for administering radiation as part of initial treatment. An outcome benefit was seen with greater extent of resection.