Prevalence,predictors, and characteristics of off‐treatment fatigue in breast cancer survivors

BACKGROUND:

Lack of consensus regarding how to identify cancer patients with significant fatigue has hampered research regarding cancer‐related fatigue (CRF).

METHODS:

Specific criteria were used to identify CRF cases in women with stage 0‐II breast cancer (BC group, n = 304). Women completed assessments before adjuvant therapy (baseline), end of adjuvant therapy (Post‐Tx), and 6 and 42 months after end of adjuvant therapy (6 and 42 Month Post‐Tx). At each, women completed a clinical interview and questionnaires assessing physical and mental health. A healthy control (HC) group with no history of BC (n = 337) completed 2 similar assessments 36 months apart.

RESULTS:

Off‐treatment CRF prevalence was 9% and 13% at the 6 and 42 Month Post‐Tx assessments, respectively. Thus, 15% of the sample evidenced off‐treatment CRF with 7% evidencing delayed onset CRF. CRF at the 6 Month Post‐Tx assessment was associated only with CRF at baseline (OR = 3.2) and Post‐Tx assessments (OR = 3.9). CRF at the 42 Month Post‐Tx assessment was associated with CRF at the Post‐Tx assessment (OR = 6.1), obesity at baseline, and several baseline measures of coping in response to fatigue. Off‐treatment CRF cases differed markedly from CRF noncases and healthy controls on a spectrum of health status indices (mean effect size >1.0 SD).

CONCLUSIONS:

Results document the prevalence of off‐treatment and delayed onset CRF, suggest the utility of a cognitive‐behavioral model of CRF, and support NCCN guidelines recommending monitoring fatigue across the cancer trajectory. Cancer 2010. © 2010 American Cancer Society.     

Multicenter imaging outcomes study of The Cancer Genome Atlas glioblastoma patient cohort: imaging predictors of overall and progression-free survival

BackgroundDespite an aggressive therapeutic approach, the prognosis for most patients with glioblastoma (GBM) remains poor. The aim of this study was to determine the significance of preoperative MRI variables, both quantitative and qualitative, with regard to overall and progression-free survival in GBM.MethodsWe retrospectively identified 94 untreated GBM patients from the Cancer Imaging Archive who had pretreatment MRI and corresponding patient outcomes and clinical information in The Cancer Genome Atlas. Qualitative imaging assessments were based on the Visually Accessible Rembrandt Images feature-set criteria. Volumetric parameters were obtained of the specific tumor components: contrast enhancement, necrosis, and edema/invasion. Cox regression was used to assess prognostic and survival significance of each image.ResultsUnivariable Cox regression analysis demonstrated 10 imaging features and 2 clinical variables to be significantly associated with overall survival. Multivariable Cox regression analysis showed that tumor-enhancing volume (P = .03) and eloquent brain involvement (P < .001) were independent prognostic indicators of overall survival. In the multivariable Cox analysis of the volumetric features, the edema/invasion volume of more than 85 000 mm³ and the proportion of enhancing tumor were significantly correlated with higher mortality (Ps = .004 and .003, respectively).ConclusionsPreoperative MRI parameters have a significant prognostic role in predicting survival in patients with GBM, thus making them useful for patient stratification and endpoint biomarkers in clinical trials.     

Prospective study of depression and fatigue in men with advanced prostate cancer receiving hormone therapy

PURPOSE: We prospectively examined the development of depressive symptoms and fatigue among men with locally advanced prostate cancer receiving hormone therapy. METHODS: Fifty-two men with advanced or recurrent prostate cancer were randomly assigned to receive either parenteral leuprolide or oral bicalutamide. Patients completed the Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) at pretreatment baseline, 6 months, and 12 months. RESULTS: Rates of at least mild depression ranged from 10.4 to 16.3% over the 12 months and were not significantly different at each time point. Mean change in BDI scores from baseline to 6 months for the entire sample was 0.91 (SE = 0.73), and from baseline to 12 months was 0.35 (SE = 0.67). Mean FSS scores increased significantly from baseline (M = 24.43, SD = 11.75) to 6 months (M = 27.93, SD = 13.52) and remained steady at 12 months (M = 27.80, SD = 14.44). There were no significant differences in depression between the two types of hormone therapy. CONCLUSION: Hormone therapy does not appear to cause clinically significant changes in depression among men with locally advanced prostate cancer. However, fatigue increased significantly over the study period.     

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma

BackgroundThe optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy.MethodsThis was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0–2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS).ResultsOne hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64–1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82–1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately.ConclusionsAdding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.

Clinical trials registration nr

ACTRN12610000915055.     

Response to chemotherapy of a radiation-induced glioblastoma multiforme

Summary Background Radiation-induced glioblastoma multiforme (GBM) is particularly resistant to treatment and therapeutic options are limited. We report a patient with a radiation-induced GBM who had a complete response to carmustine and survived for 44 months. Patients and Methods Case report of a 38-year-old man with a radiation-induced GBM that responded to carmustine. Results Our patient developed a left occipital GBM 35 years after a left cerebellar astrocytoma was treated with surgery and radiation therapy (4500 rad). The GBM was treated with subtotal resection followed by four cycles of carmustine; a complete response was achieved. He relapsed 34 months after diagnosis and with further surgery survived 44 months from his diagnosis of GBM. Conclusion GBMs may be a late complication of radiation treatment for pediatric brain tumors. If further radiotherapy is not a therapeutic option, chemotherapy may result in prolonged survival.     

Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study

We explored the feasibility of concurrent palliative chemotherapy and low-dose fractionated radiotherapy (LD-FRT) in glioblastoma multiforme (GBM). Patients with recurrent/progressive GBM at least 3 months after the end of primary radiotherapy received 0.3 Gy twice daily with cisplatin and fotemustine if progressing on temozolomide, or 0.4 Gy twice daily with temozolomide if recurrent 4-6 months later (retreatment group). Newly diagnosed GBM with gross residual mass received 30 Gy with concomitant and adjuvant temozolomide and 0.4 Gy twice daily from the second adjuvant cycle (naive group) for 2-4 cycles. Twenty-six patients were enrolled. In the retreatment group (n = 17; median LD-FRT total dose 7.2 Gy [range 2.4-11.6]), grade 3 or 4 hematological toxicity was observed in 5.9% of patients. Median follow-up time was 20 months (range 4-35). Median progression-free survival (PFS) and overall survival (OS) from the time of recurrence or progression were 4 and 8 months, respectively (OS at 6 months, 69%; at 12 months, 16.7%). In the naive group (n = 9; median LD-FRT total dose 8 Gy [range 3.2-16]), grade 3 or 4 hematological toxicity was observed in 11.1% of patients. Median follow-up time was 17 months (range 8-20)-median PFS was 9 months, with PFS at 6 months and at 1 year of 66.7% and 26.7%, respectively; and median OS was 12 months, with OS at 6 months and at 1 year of 77.8% and 34.6%, respectively. LD-FRT with concurrent chemotherapy was well tolerated.     

Fast neutrons compared with megavoltage x-rays in the treatment of patients with supratentorial glioblastoma: a controlled pilot study

The radioresistance of glioblastoma presumably results from the presence of hypoxic cells. In an attempt to overcome this problem, fast neutrons were compared in a controlled pilot study with conventional megavoltage X-rays (photons). 63 patients entered the study between January, 1973 and July, 1976, 30 patients received neutron and 33 received X-ray therapy. The overall mean survival was 11.4 months for those who received photon and 10 months for those who received neutron therapy. Survival rates at 6 and 12 months were 72 % and 36 % respectively for photon treated patients, and 77 % and 30 % for those treated with neutrons. Although neutron therapy did not improve overall survival, examination of the histological material indicated a considerably greater antitumor effect after neutron therapy than after treatment with photons. In the neutron treated group, at post-mortem examination no tumor or only minimal tumor was found in 10 of 12 patients and in one of 4 patients where tissue was obtained from a second craniotomy. In some cases, there was evidence of diffuse damage to normal brain which was in keeping with a clinical syndrome of progressive dementia without localizing signs. Dose, time, and volume factors for neutron therapy to the brain and possible ways of improving results are discussed.     

Phase 2 study of dose-intense temozolomide in recurrent glioblastoma

Background

Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O⁶-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance.

Methods

This was a multicenter, phase 2, single-arm study of temozolomide (75–100 mg/m²/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6).

Results

Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25–79 years) and a median Karnofsky performance score of 90 (range, 60–100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2).

Conclusions

Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.     

Spinal canal metastases: a late complication of glioblastoma

Summary The case of a 41 year old woman with a cerebral glioblastoma is reported who developed paraplegia due to a pathologically confirmed spinal metastasis. This and 22 other case histories from the literature suggest that spinal seeding is a rather late complication of cerebral glioblastomas that can be diagnosed on clinical grounds with the help of myelography, CSF cytology and MR imaging.     

Epithelial and pseudoepithelial differentiation in glioblastoma and gliosarcoma: a comparative morphologic and molecular genetic study

BACKGROUND: Glioblastomas exhibit a remarkable tendency toward morphologic diversity. Although rare, pseudoepithelial components (adenoid or epithelioid) or true epithelial differentiation may occur, posing a significant diagnostic challenge. METHODS: Hematoxylin and eosin-stained slides were reviewed, and immunohistochemistry and fluorescence in situ hybridization were performed. RESULTS: The patients included 38 men and 20 women. The median age at diagnosis was 57 years (interquartile range [IQR], 50 years-67 years), and the median overall survival was 7 months (IQR, 4 months-11 months). "Adenoid" glioblastomas (A-GBM) predominated (48%). True epithelial glioblastomas (TE-GBM) were next most frequent based on morphology and immunohistochemistry (35%), followed by epithelioid glioblastomas (E-GBM) (17%). Overall, 25 (43%) tumors featured a sarcomatous component. Molecular cytogenetic abnormalities identified by fluorescent in situ hybridization in A-GBM, E-GBM, and TE-GBM, respectively, included p16 deletion/-9 (60%, 71%, 64%); chromosome 10 loss (40%, 63%, 57%), chromosome 7 gain without EGFR amplification (70%, 38%, 40%), EGFR amplification (10%, 50%, 27%), PTEN deletion (10%, 25%, 29%), PDGFRA amplification (10%, 25%, 0%), and RB1 deletion/-13q (50%, 0%, 14%). Abnormalities identified by immunohistochemistry included p21 immunonegativity (60%, 25%, 93%), which was most frequent in TE-GBM (P = .008), strong nuclear p53 staining (29%, 29%, 41%), strong membranous staining for epidermal growth factor receptor (EGFR) (21%, 63%, 19%), which was most frequent in E-GBM (P = .03), and an increased frequency of p27 immunonegativity in gliosarcomas (15% negative, 85% focal) compared with tumors without sarcoma (38% strongly positive) (P = .009). CONCLUSIONS: Pseudoepithelial and true epithelial morphology are rare phenomena in GBM and may be associated with a similar poor prognosis. These tumors demonstrate proportions of molecular genetic abnormalities varying somewhat from conventional GBM.     

Pediatric giant cell glioblastoma: New insights into a rare tumor entity

Little is known about giant cell glioblastoma (GCG) in pediatric patients. The present study identified 18 pediatric patients with centrally reviewed GCG from the HIT-GBM database of the Gesellschaft für Paediatrische Onkologie und Haematologie in Germany, Austria, and Switzerland. Clinical and epidemiological data were compared with those of 178 pediatric patients with centrally reviewed glioblastoma multiforme (GBM) from the same database. In this unique series, median age, male preference, and median clinical history did not differ significantly between pediatric GCG and GBM patients. GCG showed a stronger predilection for cerebral hemispheres than did GBM, which may only partly explain the higher percentage of gross total tumor resections in GCG patients. Most surprising, the widely distributed hypothesis that GCG may imply a better prognosis than GBM could not be substantiated for our pediatric series. Future studies with larger patient numbers and molecular pathological analyses are still needed to corroborate the present findings and further elucidate the biology of GCG in children.     

Prevalence of acute and post-traumatic stress disorder and comorbid mental disorders in breast cancer patients during primary cancer care: a prospective study

This study aimed at the identification of acute and post-traumatic stress responses, and comorbid mental disorders in breast cancer patients. Structured clinical interviews for DSM-IV (SCID) were conducted post-surgery with 127 patients (t1). Screening measures were used to assess post-traumatic stress responses, anxiety, and depression at t1 and at 6 months follow-up (t2). Based on the SCID, prevalence rates were 2.4% for both, cancer-related ASD and PTSD. Experiences most frequently described as traumatic were the cancer diagnosis itself and subsequent feelings of uncertainty. Patients with lifetime PTSD (8.7%) were more likely to meet the criteria for cancer-related ASD or PTSD (OR=14.1). Prevalence estimates were 7.1% for Adjustment Disorder, 4.7% for Major Depression, 3.1% for Dysthymic Disorder and 6.3% for Generalized Anxiety Disorder. Using the screening instruments, IES-R, PCL-C and HADS, we found PTSD in 18.5% at t1 and 11.2-16.3% at t2. The estimates of anxiety and depression reveal rates of 39.6% (t1) and 32.7% (t2) for anxiety, as well as 16.0% (t1) and 13.3% (t2) for depression (t1) (cut-off> or =8). The diagnosis of a life-threatening illness has been included as a potential trauma in the DSM-IV. However, it has to be critically evaluated whether subjective feelings of uncertainty like fears of treatment count among traumatic stressors, and thus, whether the diagnosis of PTSD is appropriate in this group of cancer patients. However, a large number of women with emotional distress illustrate the need for psychosocial counseling and support in this early treatment phase.     

Mast Cellular-Type Stage-Ⅲ Glioblastoma： a Case Report

A 48-year old male patient was admitted to our hospital on December 5, 2006, because of a distending head pain over a period of 13 months. CT and MRI examinations showed that there was a space-occupying lesion in the fight frontal lobe. During the operation a tumor was found at the juncture between the grey and white matter of the fight frontal lobe, with a limpid border and without an envelop. The frontal tumor was totally excised.     

A study of concurrent radiochemotherapy with paclitaxel in glioblastoma multiforme

Despite advances in neurosurgery and radiotherapy, the prognosis of patients with glioblastoma multiforme remains poor. Reports in the literature about the radiosensitizing properties of paclitaxel stimulated the authors to conduct a study using paclitaxel concurrently with radiation in a group of 18 patients who had residual disease postoperatively. Paclitaxel was delivered weekly as an intravenous infusion in a dose of 60 mg/m ² along with radiation to the primary lesion. A total of 108 cycles of paclitaxel was given. All the patients tolerated the treatment well. The main side effects were haematological, and neuropathy which was self-limiting. The overall 1-year survival rate was 70%, with 12 patients alive at 13 months. The median survival has not yet been reached although it is more than 13 months. Thus, paclitaxel can be safely delivered concomitantly with radiation in patients with glioblastoma multiforme. Larger, randomized trials are required to establish the comparative efficacy of paclitaxel as a radiosensitizer in glioblastoma multiforme.     

Giant cell glioblastoma: A glioblastoma subtype with distinct epidemiology and superior prognosis

Giant cell glioblastoma (GC) is an uncommon subtype of glioblastoma multiforme (GBM). Consequently, the epidemiology, natural history, and factors associated with outcome are not well defined. Patients diagnosed with GC from 1988 through 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Outcomes were examined with Kaplan-Meier survival analysis and Cox models. For comparison, similar analyses were conducted for patients diagnosed with GBM. GC was identified in 1% of 16,430 patients diagnosed with either GC or GBM. Compared with GBM, GC showed similar gender and racial distributions. Likewise, tumor size and location were not significantly different between the two histologies. GC tended to occur in younger patients with a median age at diagnosis of 51 years, compared with 62 years for GBM. Additionally, patients with GC were more likely to undergo complete resection compared with patients with GBM. For both histologies, young age, tumor size, extent of resection, and the use of adjuvant radiation therapy (RT) were associated with improved survival. Cox modeling suggests the prognosis for GC is significantly superior to that for GBM (hazard ratio = 0.76; 95% confidence interval, 0.59–0.97) even after adjustment for factors affecting survival. GC is an uncommon GBM subtype that tends to occur in younger patients. Prospective data defining optimal treatment for GC are unavailable; however, these retrospective findings suggest that resection, as opposed to biopsy only, and adjuvant RT may improve survival. The prognosis of GC is superior to that of GBM, and long-term survival is possible, suggesting aggressive therapy is warranted.     

Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study

Immunostimulating oligodeoxynucleotides containing CpG motifs (CpG-ODN) have shown promising efficacy in cancer models when injected locally. In a phase I clinical trial, intratumoral infusions of CpG-ODN in glioblastoma (GBM) patients were well tolerated at doses up to 20 mg. This phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with recurrent GBMs. Patients with recurrent GBM occurring at least 3 months after radiotherapy, and previously treated with 1 or 2 regimens of chemotherapy received 20 mg of CpG-ODN (CpG-28) by convection-enhanced delivery. The primary endpoint was the percentage of patients without tumor progression 6 months after inclusion. Secondary endpoints were tolerance, survival, and radiological response. Thirty-four patients were enrolled in two centers between November 2004 and March 2006. Thirty-one patients received CpG-ODN treatment. The progression-free survival (PFS) at 6 months was 19%. One partial response and 3 minor responses were observed. The median overall survival was 28 weeks. Eight patients (24%) were alive 1 year after inclusion and 5 patients (15%) were alive after 2 years. Treatment was usually well tolerated. As reported previously, the most common toxicities were lymphopenia, mild fever, seizures, and transient neurological worsening. Despite a few cases showing a radiological response, CpG-28 showed modest activity on the 6-month PFS in this patient population. The molecular or clinical characteristics of a subgroup of patients that could potentially benefit from such an approach remain to be defined.     

Vascular heterogeneity and targeting: the role of YKL-40 in glioblastoma vascularization

Malignant glioblastomas (GBM) are highly malignant brain tumors that have extensive and aberrant tumor vasculature, including multiple types of vessels. This review focuses on recent discoveries that the angiogenic factor YKL-40 (CHI3L1) acts on glioblastoma-stem like cells (GSCs) to drive the formation of two major forms of tumor vascularization: angiogenesis and vasculogenic mimicry (VM). GSCs possess multipotent cells able to transdifferentiate into vascular pericytes or smooth muscle cells (PC/SMCs) that either coordinate with endothelial cells (ECs) to facilitate angiogenesis or assemble in the absence of ECs to form blood-perfused channels via VM. GBMs express high levels of YKL-40 that drives the divergent signaling cascades to mediate the formation of these distinct microvascular circulations. Although a variety of anti-tumor agents that target angiogenesis have demonstrated transient benefits for patients, they often fail to restrict tumor growth, which underscores the need for additional therapeutic tools. We propose that targeting YKL-40 may compliment conventional anti-angiogenic therapies to provide a substantial clinical benefit to patients with GBM and several other types of solid tumors.