The management of symptoms in advanced cancer: experience in a hospital-based continuing care unit.

The treatment received by 158 patients with advanced cancer admitted over one year to the Continuing Care Unit at the Royal Marsden Hospital has been reviewed. The unit is an integral part of the hospital and this is reflected in the fact that 46 patients (29%) received radiotherapy, hormone therapy, chemotherapy or surgery in addition to symptomatic treatment for palliation of troublesome symptoms. One hundred and thirty-one patients received oral morphine in doses ranging from 2.5 mg 4-hourly to 700 mg 4-hourly. Patients with renal or hepatic impairment required lower doses of morphine and there was a highly significant inverse relationship between morphine dose and age. Eighty-five patients (54%) received parenteral diamorphine at some time due to their inability to take oral morphine. One hundred and twenty-three patients (78%) received a co-analgesic drug and anti-emetics were required by 78 patients (49% overall; 56% of those receiving morphine). Transcutaneous electrical nerve stimulation, acupuncture and relaxation were employed in selected patients, and graduated compression sleeves were used to treat lymphoedema. These data highlight the wide range of therapeutic options available to control the symptoms of advanced cancer and also indicate that tumoricidal treatments used in conjunction with symptomatic treatments may have a significant part to play.     

EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force

The objectives have been to establish evidence-based guidelines and identify controversies regarding the management of patients with brain metastases. The collection of scientific data was obtained by consulting the Cochrane Library, bibliographic databases, overview papers and previous guidelines from scientific societies and organizations. A tissue diagnosis is necessary when the primary tumor is unknown or the aspect on computed tomography/magnetic resonance imaging is atypical. Dexamethasone is the corticosteroid of choice for cerebral edema. Anticonvulsants should not be prescribed prophylactically. Surgery should be considered in patients with up to three brain metastases, being effective in prolonging survival when the systemic disease is absent/controlled and the performance status is high. Stereotactic radiosurgery should be considered in patients with metastases of 3–3.5 cm of maximum diameter. Whole-brain radiotherapy (WBRT) after surgery or radiosurgery is debated: in case of absent/controlled systemic cancer and Karnofsky Performance score of 70 or more, one can either withhold initial WBRT or deliver early WBRT with conventional fractionation to avoid late neurotoxicity. WBRT alone is the treatment of choice for patients with single or multiple brain metastases not amenable to surgery or radiosurgery. Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors.     

Inhibition by sumatriptan of central trigeminal neurones only after blood-brain barrier disruption.

1. The 5-hydroxytryptamine (5-HT1)-like agonist, sumatriptan, is highly efficient in the relief of migraine headache and its accompanying symptoms. 2. Experimental evidence has indicated that its site of action may be on the cranial vessels or on the trigeminal innervation of the cranium, or both, since sumatriptan does not pass the blood-brain barrier easily under normal circumstances. It is, however, not clear whether the blood-brain barrier is normal or abnormal during a migraine attack. 3. In this study, single unit activity and trigeminal somatosensory evoked potentials in central trigeminal neurones were monitored during electrical stimulation of the superior sagittal sinus. 4. Intravenous administration of sumatriptan (100 micrograms kg-1) did not alter trigeminal evoked activity unless the permeability of the blood-brain barrier had been increased by infusion of an hyperosmolar mannitol solution. After blood-brain barrier disruption, sumatriptan decreased the peak-to-peak amplitude of evoked potentials by 40 +/- 6% and the probability of firing of single units by 30 +/- 9%. Mannitol infusions alone in control animals caused no changes in evoked potentials or single unit activity. 5. The data suggest that in normal circumstances sumatriptan does not have sufficient access to trigeminal neurons to alter their function.     

Phosphatidylinositol 3-kinase inhibitors prevent mouse cytotoxic T-cell development in vitro

To become competent killer cells, CD8(+) T cells require stimulation through signal transduction pathways associated with the T-cell receptor, costimulatory molecules such as CD28, and cytokine receptors such as the interleukin (IL)-2 receptor. We used wortmannin and LY294002, two inhibitors of phosphatidylinositol 3-kinase (PI3-K), to study the role of PI3-K in mouse cytotoxic T-lymphocyte (CTL) induction in response to mitogenic anti-CD3 antibody. Anti-CD3-induced CD8(+) T-cell proliferation and CTL development were inhibited dose dependently by both PI3-K inhibitors. IL-2 synthesis by anti-CD3-activated CD8(+) T cells was also diminished by PI3-K inhibition. PI3-K inhibition resulted in a modest decrease in anti-CD3-induced CD4(+) T-cell proliferation but failed to affect IL-2 expression by anti-CD3-activated CD4(+) T cells. PI3-K inhibition during CTL induction resulted in decreased levels of mRNAs coding for granzyme B, perforin, and Fas ligand. In addition, CTL induced in the presence of PI3-K inhibitors failed to conjugate normally with P815 target cells. Exogenous IL-2 did not reverse the effects of PI3-K inhibition on CD8(+) T-cell proliferation and CTL induction. These results support the conclusion that PI3-K activation is involved in T-cell receptor, CD28, and IL-2 receptor signaling of CD8(+) T cells. PI3-K is, therefore, an important component of multiple signal transduction pathways involved in CTL generation.     

The immunohistochemical assessment of hypoxia, vascularity and proliferation in bladder carcinoma.

BACKGROUND AND PURPOSE: Hypoxia and proliferation are important determinants of radiation responsiveness; prospective measures of these before radiotherapy may enable individualisation of treatment schedules. Immunohistochemical techniques offer a potential means of achieving this in routine biopsy material. MATERIAL AND METHODS: Cellular hypoxia as measured by pimonidazole fixation and immunohistochemistry has been evaluated in a series of human bladder cancers with dual staining of sections for pimonidazole and either the vascular markers, CD31/34, or proliferation markers, Ki-67 or cyclin A. Twenty one tumour specimens were examined suitable for the double staining technique. RESULTS: The median hypoxic fraction was 9% (range 0-38). Seven tumours did not stain for pimonidazole and 11 exhibited necrosis. The mean vascular density ranged from 16.7 to 160.6 vessels per mm2. The median hot spot count was 30 (range 16-43). There was a statistically significant increase in vessel density in hypoxic compared to oxic regions measured by both vessel density (P = 0.02) and hot spot count (P = 0.004). Proliferation indices decreased from oxic to hypoxic areas close to blood vessels. CONCLUSIONS: We have demonstrated that bladder cancer exhibits a range of hypoxia, proliferation and vascular density which may be used to form the basis for patient selection for hypoxia modification, accelerated radiotherapy and vascular targeting agents.     

Metastatic spinal cord compression: radiotherapy outcome and dose fractionation.

BACKGROUND AND PURPOSE: No standard dose fractionation has been defined for metastatic spinal cord compression. This retrospective analysis was undertaken to explore the impact of hypofractionated treatment compared to conventional multifraction treatment. MATERIALS AND METHODS: One hundred and two consecutive patients referred to Mount Vernon Cancer Centre with metastatic spinal canal compression confirmed on MR scan in 95% with median age 68 years (range 32-90) and main primary tumour types breast (28%), prostate (28%) and lung (20%); 51% of patients were fully ambulant at diagnosis, 41% ambulant but with paraparesis and 9% had complete paraplegia. Spinal radiotherapy was given delivering a single dose in 32% and 20 Gy in five fractions in 64%. RESULTS: The median survival was 3.5 months; survival was significantly related to primary site and motor function at presentation. Normal ambulation was achieved in 58% at 2 weeks and 71% up to 2 months after treatment. No patient who presented with paraplegia regained function. At presentation 59% of patients had severe pain, which fell to 8% at 2 weeks. Comparing those patients who received one or two dose treatments with those who received protracted fractionation, the two groups were matched for age, sex, primary site and site of compression. Relatively more patients treated with one or two doses had paraplegia; 19% vs. 3%. Despite this outcome in the two groups was equivalent for motor and sphincter function and pain control. CONCLUSIONS: Metastatic spinal canal compression carries a poor prognosis. Urgent treatment will maintain and improve motor function in patients presenting ambulant but those who have paraplegia at presentation do not improve and have a very short survival. In this series no difference in outcome was seen between patients treated with one or two radiation doses compared to multifraction treatment; a randomised trial comparing fractionation schedules would be justified.     

A Randomized,Double-Blind,Dose-Finding,Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

Background

Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile.

Objective

To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases.

Design, setting, and participants

In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥50% in baseline prostate-specific antigen (PSA) levels.

Outcome measurements and statistical analysis

Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups.

Results and limitations

The study met its primary end point with a statistically significant dose–response relationship in confirmed ≥50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p = 0.0297). A ≥50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p < 0.0001). The most common treatment-related AEs (≥10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline.

Conclusions

Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses.

Trial registration

ClinicalTrials.gov: NCT00337155.     

ASO Author Reflections: Axillary Management in Mastectomy Patients with Limited Nodal Burden

Annals of Surgical Oncology -