The views of patients with brain cancer about palliative care: a qualitative study.

BACKGROUND: Palliative care, a specialty aimed at providing optimal care to patients with life-limiting and chronic conditions, has several benefits. Although palliative care is appropriate for neurosurgical conditions, including brain cancer, few studies have examined the views of brain cancer patients about palliative care. We aimed to explore the thoughts of brain cancer patients about palliative care, their opinions about early palliative care, and their preferred care setting. METHODS: Semi-structured interviews and the qualitative research methodologies of grounded theory were used to explore perceptions of palliative care on the part of 39 brain cancer outpatients. RESULTS: Seven overarching actions emerged: ■Patients would prefer to receive palliative care in the home.■Increased time with caregivers and family are the main appeals of home care.■Patients express dissatisfaction with brief and superficial interactions with health care providers.■Patients believe that palliative care can contribute to their emotional well-being.■Patients are open to palliative care if they believe that it will not diminish optimism.■There is a preconceived idea that palliative care is directly linked to active dying, and that supposed link generates fear in some patients.■Patients prefer to be educated about palliative care as an option early in their illness, even if they are fearful of it. CONCLUSIONS: Overall, when educated about the true meaning of palliative care, most patients express interest in accessing palliative care services. Although the level of fear concerning palliative care varies in patients, most recognize the associated benefits.

Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

Canadian recommendations for the treatment of glioblastoma multiforme.

RECOMMENDATION 1: Management of patients with glioblastoma multiforme (GBM) should be highly individualized and should take a multidisciplinary approach involving neuro-oncology, neurosurgery, radiation oncology, and pathology, to optimize treatment outcomes. Patients and caregivers should be kept informed of the progress of treatment at every stage. RECOMMENDATION 2: Sufficient tissue should be obtained during surgery for cytogenetic analysis and, whenever feasible, for tumour banking. RECOMMENDATION 3: Surgery is an integral part of the treatment plan, to establish a histopathologic diagnosis and to achieve safe, maximal, and feasible tumour resection, which may improve clinical signs and symptoms. RECOMMENDATION 4: The preoperative imaging modality of choice is magnetic resonance imaging (MRI) with gadolinium as the contrast agent. Other imaging modalities, such as positron emission tomography with [(18)F]-fluoro-deoxy-d-glucose, may also be considered in selected cases. Postoperative imaging (mri or computed tomography) is recommended within 72 hours of surgery to evaluate the extent of resection. RECOMMENDATION 5: Postoperative external-beam radiotherapy is recommended as standard therapy for patients with gbm. The recommended dose is 60 Gy in 2-Gy fractions. The recommended clinical target volume should be identified with gadolinium-enhanced T1-weighted mri, with a margin in the order of 2-3 cm. Target volumes should be determined based on a postsurgical planning MRI. A shorter course of radiation may be considered for older patients with poor performance status. RECOMMENDATION 6: During RT, temozolomide 75 mg/m(2) should be administered concurrently for the full duration of radio-therapy, typically 42 days. Temozolomide should be given approximately 1 hour before radiation therapy, and at the same time on the days that no radiotherapy is scheduled. RECOMMENDATION 7: Adjuvant temozolomide 150 mg/m(2), in a 5/28-day schedule, is recommended for cycle 1, followed by 5 cycles if well tolerated. Additional cycles may be considered in partial responders. The dose should be increased to 200 mg/m(2) at cycle 2 if well tolerated. Weekly monitoring of blood count is advised during chemoradiation therapy in patients with a low white blood cell count. Pneumocystis carinii pneumonia has been reported, and prophylaxis should be considered. RECOMMENDATION 8: For patients with stable clinical symptoms during combined radiotherapy and temozolomide, completion of 3 cycles of adjuvant therapy is generally advised before a decision is made about whether to continue treatment, because pseudo-progression is a common phenomenon during this time. The recommended duration of therapy is 6 months. A longer duration may be considered in patients who show continuous improvement on therapy. RECOMMENDATION 9: Selected patients with recurrent gbm may be candidates for repeat resection when the situation appears favourable based on an assessment of individual patient factors such as medical history, functional status, and location of the tumour. Entry into a clinical trial is recommended for patients with recurrent disease. RECOMMENDATION 10: The optimal chemotherapeutic strategy for patients who progress following concurrent chemoradiation has not been determined. Therapeutic and clinical-molecular studies with quality of life outcomes are needed.

Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival.

PURPOSE: Anti-Hu antibodies (HuAb) recognize antigens expressed by neurons and small-cell lung cancer (SCLC). High titers of HuAb were initially reported in serum from patients with paraneoplastic encephalomyelitis/sensory neuropathy (PEM/SN) and SCLC. Preliminary studies have indicated that some SCLC patients without PEM/SN harbor low titer of HuAb in their serum, and that the SCLC of these patients may grow more indolently. Based on these observations, we conducted a multicenter prospective study of SCLC patients without PEM/SN to determine the incidence and prognostic implications of HuAb. METHODS: Serum samples were collected at diagnosis of SCLC in 196 patients without PEM/SN. HuAb were determined by immunoblot of purified recombinant HuD antigen. RESULTS: HuAb were detected in 32 (16%) of the 196 patients. Of the 170 patients who received treatment for the tumor, 27 (16%) were HuAb positive. HuAb was associated with limited disease stage (59.3% v 38.6%; P = .047), complete response to therapy (55.6% v 19.6%; P < .001), and longer survival (14.9 v 10.2 months; P = .018). In a logistic regression analysis, HuAb status was an independent predictor of complete response induction. The probability of achieving a complete response was more than five times higher in HuAb-positive than in HuAb-negative patients (odds ratio, 5.4; 95% confidence interval, 1.71 to 16.89; P = .004). Cox multivariate analysis indicated that HuAb status was not independently associated with survival. CONCLUSION: The presence of HuAb at diagnosis of SCLC is a strong and independent predictor of complete response to treatment. This feature accounts for the association between HuAb and longer survival.

Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors.

PURPOSE: To evaluate a strategy that avoids radiotherapy in children less than 6 years of age with newly diagnosed malignant brain tumors, by administering myeloablative consolidation chemotherapy with autologous bone marrow reconstitution (ABMR) after maximal surgical resection and conventional induction chemotherapy. PATIENTS AND METHODS: Between March 1991 and April 1995, 62 children (median age, 30 months) with newly diagnosed malignant brain tumors were enrolled onto this trial. Children received conventional induction chemotherapy with vincristine, cisplatin, cyclophosphamide, and etoposide, repeated every 3 weeks for five cycles. Children without disease progression on induction chemotherapy were offered consolidation with myeloablative chemotherapy that incorporated carboplatin, thiotepa, and etoposide followed by ABMR. Irradiation was used only for residual tumor at consolidation or for progressive/recurrent disease. RESULTS: Induction chemotherapy was well tolerated by most patients; however, progression was noted in 17 children (27%) and four (6%) died of treatment complications. Of 37 children who received consolidation chemotherapy with ABMR, 15 are free of disease progression (median post-ABMR without further treatment, >44 months). The remaining 22 all progressed within 15 months of ABMR; three of 37 (8%) died of treatment-related complications. The 3-year overall survival (OS) and event-free survival (EFS) rates from diagnosis for all children are 40% (95% confidence interval [CI], 28% to 52%) and 25% (95% CI, 13% to 37%), respectively. Radiotherapy was administered to 19 of 62 children: 17 for progressive disease (PD) and two for residual disease at the time of ABMR. CONCLUSION: A significant proportion of children with malignant brain tumors can avoid radiotherapy and prolonged maintenance chemotherapy yet still achieve durable remission with this brief intensive chemotherapy regimen.

Low-grade oligodendroglioma responds to chemotherapy.

We administered chemotherapy in standard and intensified formulations of procarbazine, lomustine (CCNU), and vincristine to nine symptomatic patients with low-grade oligodendroglioma. Eight patients were treated with chemotherapy at presentation and one was treated for a recurrence after radiotherapy had failed. All patients improved by clinical or MRI criteria, or both. No patient deteriorated while in therapy and the responses were sustained without radiotherapy for a median of 35 months (range, 22-45) in all surviving patients treated at presentation. Chemotherapy was well tolerated; all patients developed myelosuppression, but only those receiving the intensified regimen required dose reduction or premature discontinuation of treatment. As with recurrent and anaplastic oligodendroglioma, low-grade oligodendroglioma responds to chemotherapy.

111Indium-diethylenetriamine pentaacetic acid cerebrospinal fluid flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases.

Abnormal CSF flow can impair the distribution of intrathecally administered drugs. We examined the relationship between 111indium-diethylenetriamine pentaacetic acid (111In-DTPA) CSF flow studies and methotrexate levels in ventricular and lumbar CSF and correlated these findings with outcome in patients with leptomeningeal metastases (LM). Seven men and 10 women with LM (10 solid tumors, 6 lymphoma, 1 leukemia) received 12 mg methotrexate and 0.5 mCi 111In-DTPA by intra-Ommaya injection; images were obtained immediately and after 4, 24, and 48 hours. Ventricular and lumbar CSF methotrexate and radioactivity levels were measured 6 hours after injection. Thirteen patients had abnormal CSF flow studies, 9 with multiple sites of obstruction. CSF flow obstruction was observed at ventricular outlets in 13 patients, cerebral convexities in 9 and in the spine in 2. With one exception, all obstructions were explicable by tumor deposits on MRIs. For all patients, ventricular and lumbar methotrexate and radioactivity levels correlated closely. Three patients with a normal CSF flow study are alive at 15+, 7.5+, and 3.9+ months from treatment. Of 12 with abnormal CSF flow studies, 11 are dead a median of 2 months from diagnosis. Two patients had diffusely delayed flow studies and both developed methotrexate leukoencephalopathy. CSF flow studies using 111In-DTPA reliably predict distribution of intrathecal methotrexate. Abnormal flow studies correlate with structural abnormalities, are an unfavorable prognostic factor, and may predict intrathecal chemotherapy toxicity.

Fine tuning of linear accelerator accessories for stereotactic radiotherapy.

PURPOSE: Experience with the University of Wisconsin's stereotactic radiotherapy (SRT) accessory system was applied to build a new system, facilitate alignment of linac photon beams with a Brown-Roberts-Wells (BRW) stereotaxy, and increase the versatility and stability of the stereotaxy. METHODS AND MATERIALS: High tensile strength stainless steel was used in the floor stand to increase the range of gantry rotation relative to ranges allowed by truss-mounted stands. The collimator assembly and floor stand were each fitted with two-axis gimbal and translation adjustments in addition to the floor stand's three-axis adjustments. The head ring positioning assembly was fitted with two braces to prevent the head ring from deforming with patient motion. Six MV linac photon beam characteristics were measured with a computer-controlled scanning system and a diode in water, at source to surface distances (SSD) of 80 and 100 cm, and for 13 divergent collimators ranging in diameter from 1-4 cm at 100 cm SSD. Quality assurance software was applied to screen data for questionable consistency or symmetry. Integrity of the stereotaxy was evaluated with target simulation films and repeated measurements which were part of the quality assurance of clinical treatments. A method was developed using a glass etched contact reticle to obtain average simulated target to beam center distances (delta av) from target simulation films. RESULTS AND CONCLUSION: New aspects of the current system have improved the ability to fine tune and analyze stereotactic alignment. Beam characteristics met stringent output criteria and penumbral widths were the same or narrower than penumbral widths reported elsewhere. The precision of measuring delta av was 0.1 mm, and delta av averaged over 50 target simulation films was 0.7 +/- 0.1 mm. Results suggest that it may be useful to determine delta av from target simulation films with the method described here.

Human papillomavirus detection by hybrid capture and its possible clinical use.

AIMS: To determine the sensitivity of the hybrid capture method for human papillomavirus (HPV) detection and potential clinical uses as a screening method for the identification of cervical intraepithelial neoplasia. METHODS: The presence of oncogenic types of HPV was tested for in samples taken from the cervix at colposcopy, and compared with detection by polymerase chain reaction (PCR) in 60 patients. Both sets of results were corrected with the pathology determined by biopsy and smear cytology. RESULTS: Hybrid capture detection showed 86% agreement with PCR. Eighty three percent of CIN 3 lesions, 62% of CIN 2, 59% of CIN 1 and 21% of normal controls were positive for oncogenic HPV types. CONCLUSION: The hybrid capture detection method is reliable, sensitive, and easy to use. The addition of HPV testing to cytological screening would detect a greater proportion of cervical dysplasia with a higher false positive rate.

A new and sensitive method of screening for human papillomavirus infection.

Human papillomaviruses (HPVs) have been implicated in the development of cervical cancer, and HPV screening may one day supplement cytologic analysis of cervical samples. Detection of the small amounts of HPV DNA in cervical scrapes has been very difficult. The polymerase chain reaction is a new technique that can specifically amplify target DNA to facilitate its detection. We have amplified a region of HPV type 16 DNA using this technique and have shown the method to be both specific and sensitive (a tenfold improvement when compared with Southern blotting). Among 21 cervical scrapes, five from women with normal smears and 16 from women with dyskaryotic smears, HPV 16 DNA was present in scrapes from two women (40%) with normal smears and in scrapes from 12 women (75%) with dyskaryotic smears. The polymerase chain reaction technique is rapid, requires no radioactive probes, and should be the method of choice in future studies to determine the prevalence of HPV infection of the cervix.

Laser excision rather than vaporization: the treatment of choice for cervical intraepithelial neoplasia.

We are concerned that the use of ablative therapy in the treatment of cervical intraepithelial neoplasia may lead to a failure to diagnose early invasive carcinoma. In view of this, since June 1986, 196 patients considered suitable for laser vaporization were treated by a shallow laser excision cone biopsy instead. The mean age of the women treated was 31 years, and the mean length of the excised specimen, measured after fixation, was 14 mm. All procedures were completed in the colposcopy clinic and took no longer to perform than vaporization. The complication rate was low, and an excellent specimen was available for pathologic examination. In this series, histology on the excised cone revealed that two patients had microinvasive carcinoma and one had adenocarcinoma in situ. In addition, 16 patients had a lesion two or three grades worse on the laser excision biopsy than was predicted by the colposcopically directed biopsy. Because of the inaccuracy of colposcopic biopsy, we now recommend a small laser excision cone biopsy as the treatment of choice for all patients with cervical intraepithelial neoplasia.

The role of subcutaneous luteinising hormone releasing hormone in the induction of ovulation.

Induction of ovulation using pulsatile luteinising hormone releasing hormone (LHRH) has been performed in 53 anovulatory women who had previously failed to respond to clomiphene. Pelvic ultrasound imaging prior to treatment provided an accurate means of predicting the subsequent response to subcutaneous and intravenous therapy and was of particular value in differentiating patients with ovarian enlargement due to multiple intraovarian follicles. Subcutaneous administration was appropriate in the majority of patients. Thirty-eight conceptions have been confirmed.

Infertility, megalocystic and polycystic ovaries: differential response to LHRH therapy.

A group of anovulatory women have been identified as being particularly difficult to treat with pulsatile luteinising hormone releasing hormone (LHRH). Further investigation shows that sub-division into two groups is possible on the basis of ovarian morphology on ultrasound imaging. Ovulation can be successfully induced in women with megalocystic ovaries and 14 of those women treated conceived.

Ultrasound assessment of changes in the ovary and the uterus during LHRH therapy.

Twenty-seven women with secondary amenorrhoea have been treated with pulsatile subcutaneous luteinising hormone releasing hormone (LHRH). Serial ultrasonic observations of increasing follicular diameters and changes in the size of the uterus have been recorded. The rate of the increase of the diameter of dominant follicles in LHRH induced cycles is identical to that observed in women undergoing spontaneous cycles. An interesting correlation was observed between follicular diameter and uterine size. The correlation suggests that uterine size measured ultrasonically can be used as a bio-assay of follicular oestradiol production. Uterine growth continues throughout the luteal phase of conception cycles and can be used as a very early sign of pregnancy.

Role of colposcopy in the diagnosis and outpatient treatment of cervical intraepithelial neoplasia.

One hundred and seventy nine women with abnormal smears referred for colposcopy to the Samaritan Hospital were studied. After confirming CIN on repeat smear, colposcopy and histology, cone biopsy was carried out. One hundred and twenty one patients (68%) had treatment either with electrical loop diathermy under local anaesthesia (105 patients, 59%) or laser excision of transformation zone under general anaesthesia as a day case (16 patients, 9%). Cone biopsy was done in 121 patients (32%). We conclude that colposcopy is a valuable tool in combination with cytology and histology for diagnosis and delineating the extent of CIN, thus avoiding unnecessary cone biopsies particularly in women of child bearing age. The majority of patients were treated by an outpatient procedure, which is easy to learn, safe, effective and inexpensive.

Pretreatment ADC histogram analysis is a predictive imaging biomarker for bevacizumab treatment but not chemotherapy in recurrent glioblastoma.

BACKGROUND AND PURPOSE: Pre-treatment ADC characteristics have been shown to predict response to bevacizumab in recurrent glioblastoma multiforme. However, no studies have examined whether ADC characteristics are specific to this particular treatment. The purpose of the current study was to determine whether ADC histogram analysis is a bevacizumab-specific or treatment-independent biomarker of treatment response in recurrent glioblastoma multiforme. MATERIALS AND METHODS: Eighty-nine bevacizumab-treated and 43 chemotherapy-treated recurrent glioblastoma multiformes never exposed to bevacizumab were included in this study. In all patients, ADC values in contrast-enhancing ROIs from MR imaging examinations performed at the time of recurrence, immediately before commencement of treatment for recurrence, were extracted and the resulting histogram was fitted to a mixed model with a double Gaussian distribution. Mean ADC in the lower Gaussian curve was used as the primary biomarker of interest. The Cox proportional hazards model and log-rank tests were used for survival analysis. RESULTS: Cox multivariate regression analysis accounting for the interaction between bevacizumab- and non-bevacizumab-treated patients suggested that the ability of the lower Gaussian curve to predict survival is dependent on treatment (progression-free survival, P = .045; overall survival, P = .003). Patients with bevacizumab-treated recurrent glioblastoma multiforme with a pretreatment lower Gaussian curve > 1.2 µm(2)/ms had a significantly longer progression-free survival and overall survival compared with bevacizumab-treated patients with a lower Gaussian curve < 1.2 µm(2)/ms. No differences in progression-free survival or overall survival were observed in the chemotherapy-treated cohort. Bevacizumab-treated patients with a mean lower Gaussian curve > 1.2 µm(2)/ms had a significantly longer progression-free survival and overall survival compared with chemotherapy-treated patients. CONCLUSIONS: The mean lower Gaussian curve from ADC histogram analysis is a predictive imaging biomarker for bevacizumab-treated, not chemotherapy-treated, recurrent glioblastoma multiforme. Patients with recurrent glioblastoma multiforme with a mean lower Gaussian curve > 1.2 µm(2)/ms have a survival advantage when treated with bevacizumab.

Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme.

Recommendation 1: Multidisciplinary ApproachTo optimize treatment outcomes, the management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neuro-oncology, and allied health professions.Recommendation 2: ImagingThe standard imaging modality for assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (mri). Tumour recurrence should be assessed according to the criteria set out by the Response Assessment in Neuro-Oncology Working Group. The optimal timing and frequency of mri after chemoradiation and adjunctive therapy have not been established.Recommendation 3: Pseudo-progressionProgression observed by mri after chemoradiation can be pseudo-progression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing mri within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required re-operation. Adjuvant temozolomide should be continued and follow-up imaging obtained.Recommendation 4: Repeat SurgerySurgery can play a role in providing symptom relief and confirming tumour recurrence, pseudo-progression, or radiation necrosis. However, before surgical intervention, it is essential to clearly define treatment goals and the expected impact on prognosis and the patient's quality of life. In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient.Recommendation 5: Re-irradiationRe-irradiation is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma.Recommendation 6: Systemic TherapyClinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy, including temozolomide rechallenge or anti-angiogenic therapy, may be considered. Combination therapy is still experimental; optimal drug combinations and sequencing have not been established.

Chemotherapy for low-grade gliomas.

The management of low-grade oligodendrogliomas and oligoastrocytomas has been further complicated by recent reports documenting the chemosensitivity of these tumours. Preliminary results suggest that low-grade oligodendroglial tumours are less dramatic and predictable in their response to chemotherapy than their anaplastic counterparts. Nonetheless, the use of chemotherapy as initial treatment for these indolent neoplasms has inherent appeal, particularly if this strategy permits the delay or elimination of cranial irradiation. Before the use of chemotherapy becomes standard initial therapy for these neoplasms, further efforts will be required to describe in greater detail the susceptibility of these tumours to chemotherapy, document the delayed toxicities of chemotherapy for low-grade oligodendrogliomas, identify the most therapeutic agents or regimens, and correlate clinical and radiographic response with molecular markers of chemosensitivity.