Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey.

Breakthrough pain (BKP) is a transitory flare of pain that occurs on a background of relatively well controlled baseline pain. Previous surveys have found that BKP is highly prevalent among patients with cancer pain and predicts more severe pain, pain-related distress and functional impairment, and relatively poor quality of life. An international group of investigators assembled by a task force of the International Association for the Study of Pain (IASP) evaluated the prevalence and characteristics of BKP as part of a prospective, cross-sectional survey of cancer pain. Fifty-eight clinicians in 24 countries evaluated a total of 1095 patients with cancer pain using patient-rated items from the Brief Pain Inventory (BPI) and observer-rated measures. The observer-rated information included demographic and tumor-related data, the occurrence of BKP, and responses on checklists of pain syndromes and pathophysiologies. The clinicians reported BKP in 64.8% of patients. Physicians from English-speaking countries were significantly more likely to report BKP than other physicians. BKP was associated with higher pain scores and functional interference on the BPI. Multivariate analysis showed an independent association of BKP with the presence of more than one pain, a vertebral pain syndrome, pain due to plexopathy, and English-speaking country. These data confirm the high prevalence of BKP, its association with more severe pain and functional impairment, and its relationship to specific cancer pain syndromes. Further studies are needed to characterize subtypes of BKP. The uneven distribution of BKP reporting across pain specialists from different countries suggests that more standardized methods for diagnosing BKP are needed.

Palliative venting gastrostomy in malignant intestinal obstruction.

This retrospective clinical study reports on the experience of palliative venting gastrostomy (PVG) in an integrated acute teaching hospital and hospice-based palliative care service over a seven-year period (1989-97). PVG was performed for 51 patients with refractory nausea and vomiting resulting from varying degrees and levels of persisting or intermittent malignant bowel obstruction. There were 32 females and 19 males; the mean age was 61 years (range 25-86 years). All patients had advanced and incurable cancer with intra-abdominal spread, originating from the following primary sites: colon and rectum (27), ovary (16), breast (2), pancreas (2), and other (4). The venting gastrostomy tube was inserted endoscopically by a railroading technique in 46 patients (using a 16- to 20-French Dobhoff PEG tube), at open laparotomy in four cases and under radiological (abdominal computerized tomography) control in one case. Endoscopic insertion was attempted and abandoned for technical reasons in a further two cases. The median survival of all 51 patients from the time of gastrostomy insertion was 17 days (range 1-190). In 47/51 (92%), the symptoms of nausea and vomiting were relieved by the procedure, and these patients experienced restoration of some level of oral soft food and fluid intake. Twenty patients were discharged home, and six died at home. In a small group of highly selected patients, for whom pharmacological measures failed to palliate the effects of malignant bowel obstruction, PVG was shown to be a safe and effective means of abolishing or substantially improving vomiting. Provided that the intervention is appropriate to the given clinical situation and acceptable to the patient, it should be considered.

Opioid substitution to reduce adverse effects in cancer pain management.

OBJECTIVE: To assess the effect of opioid substitution (substituting one member of the opioid class for another) on the incidence and severity of adverse effects in palliative care patients who experience unacceptable, refractory adverse effects when taking an opioid drug. DESIGN: Prospective audit of clinical records. SETTING: Palliative Care Program, Monash Medical Centre, Melbourne, Victoria (comprising an acute 10-bed palliative care unit and a palliative care consultative service). PATIENTS: All palliative care inpatients and patients referred to the consultative service who underwent opioid substitution between February 1996 and June 1997. OUTCOME MEASURES: Adverse effects and pain control profiles before and after opioid substitution. RESULTS: 55 opioid substitutions were undertaken in 49 patients. 49 substitutions were for adverse effects. The substitution produced partial or complete relief from confusion in 18 of 25 cases, from nausea and vomiting in 13 of 19, and from drowsiness in 8 of 15. Substitution also abolished myoclonus associated with renal failure in one patient. CONCLUSION: We found that the incidence and severity of adverse effects differed between opioids in the same patient. A trial of opioid substitution (usually in consultation with a specialist pain or palliative care unit and with auditing of outcomes) should be considered for patients with intolerable, refractory adverse effects of opioids.

Statistical methods for assessing differential vaccine protection against human immunodeficiency virus types.

The human immunodeficiency virus type 1 (HIV-1) is extremely diverse. In assessing the utility of an HIV-1 vaccine, an important issue is the possibility of differential protection. We discuss statistical methods of inferring how the vaccine efficacy may vary with viral type from data that would be collected from a randomized, double-blind, placebo-controlled preventive vaccine efficacy trial. Detailed characterization of virus isolated from individuals infected during the trial will be available. We focus on the highly simplified case in which the viral characteristics are summarized by a single feature, which may be nominal, or a scalar quantity that represents distance between the isolate and the prototype virus or viruses used in the vaccine preparation. We consider discrete categorical and continuous response models for this quantity and identify models whose parameters can be interpreted as log ratios of strain-specific relative risks of infection in a prospective model for HIV-1 exposure and transmission. Methods of inference are described for the multinomial logistic regression (MLR) model for discrete categorical response, and a new semiparametric model which can be viewed as a continuous analog of the MLR model is introduced. The methods are illustrated by application to HIV-1 and hepatitis B vaccine trial data.

Neuropsychological and pharmacokinetic assessment of hospice inpatients receiving morphine.

Eighteen inpatients receiving morphine for cancer pain in a palliative care unit were recruited to a study employing a range of neuropsychological tests to assess cognitive function. The tests employed were National Adult Reading Test, Williams Delayed Recall Test, Immediate Memory for Digits, Trailing Making Test, and the Digit Symbol Substitution Test. These data were correlated with biochemical tests of renal and hepatic function, morphine dose, route of administration, plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations. Despite having no clinical evidence of impairment of cognitive function, the level of current intellectual functioning (Symbol Digit Substitution Test) was on average two standard deviations below normal. Immediate memory appeared to be well preserved, but Delayed Recall and Trailing Making Test scores were significantly above normal. There was no significant correlation between morphine dose, or plasma morphine and M3G and M6G concentrations, and the neuropsychological test results, although a weak correlation was found between plasma morphine concentration and digits forward (r = -0.47, p < 0.05) and Digit Symbol Substitution scores (r = -0.46, p < 0.05). Seven patients had some degree of nausea or vomiting, ascribed as an opioid adverse effect, and had higher serum creatinine concentrations, worse neuropsychological performance, and significantly higher plasma M3G concentrations (p < 0.05). These data provide some evidence to suggest that cognitive functioning in patients with advanced cancer receiving morphine may be significantly impaired despite apparent clinical normality. From these data it is not possible to determine what relative causal contribution the disease and the drug made to these observations, although renal function, plasma morphine, and M3G concentrations may be important. Future research should address a broad range of neuropsychological testing to assist in the modification of practices aimed at enhancement of quality of life, such as opioid substitution or rotation.

Thrombopoietin mobilizes CD34+ cell subsets into peripheral blood and expands multilineage progenitors in bone marrow of cancer patients with normal hematopoiesis.

Thrombopoietin (TPO), the primary regulator of megakaryocytopoiesis, also mediates biologic effects in vitro on hematopoietic cells more primitive than those committed to the megakaryocyte (MK) lineage. To assess the spectrum of hematopoietic effects of recombinant human (rh)TPO in vivo, we evaluated its proliferative effect on bone marrow (BM) progenitor cells, its maturation effect on BM MKs, and its mobilizing effect on peripheral blood (PB) progenitor cells during a phase I clinical laboratory investigation in which rhTPO was administered to cancer patients with normal hematopoiesis. Twelve patients received a single dose of rhTPO (0.3, 0.6, 1.2, or 2.4 microg/kg of body weight) prior to chemotherapy. BM and PB samples from these patients were analyzed 1 to 2 days before (baseline) and 7 days after rhTPO administration. At higher doses (1.2-2.4 microg/kg), rhTPO produced increased concentrations of primitive CD34+Thy-1+Lin-cells (mean 2.1-fold), CD34+mpl+ cells (mean 5.2-fold), CD34+CD41+CD14- promegakaryoblasts (mean 2.9-fold), and myeloerythroid colony-forming cells (mean threefold) in BM. No significant increases in the frequency of BM colony-forming unit (CFU)-MK were observed. Elevated numbers of both immature (2N-8N) and more mature (64N and 128N) CD41+ MKs were detected in BM, with modal ploidy remaining at 16N. Higher doses of rhTPO (1.2-2.4 microg/kg) also induced increased concentrations of CD34+ cell subsets in PB, including both primitive CD34+Thy-1+Lin- (mean 8.8-fold) and MK lineage-committed CD34+CD41+CD14- cells (mean 14.6-fold) as well as various myeloerythroid colony-forming cells (mean 3.6- to 5.5-fold). These results demonstrate that rhTPO given as a single dose not only promotes proliferation and maturation of cells of the MK lineage, but also expands the pool of BM primitive hematopoietic cells. In addition, rhTPO induces mobilization of hematopoietic progenitors into peripheral circulation. The extent to which such multilineage effects on human progenitor cells will contribute to clinical efficacy remains to be determined.

Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection.

BACKGROUND: Most individuals infected with HIV-1 show disease progression despite both cellular and humoral immune responses. We investigated whether immunisation of patients who had symptomless HIV-1 infection with an envelope subcomponent vaccine (MNrgp120) to augment immune response can slow progression of HIV-1 disease. METHODS: In a randomised, double-blind, placebo-controlled trial, carried out in university infectious disease clinics and community infectious disease practices, we enrolled 573 HIV-infected patients with CD4 counts above 600 cells/microL (0.6 x 10(9)/L). Patients received 600 micrograms vaccine or placebo by intramuscular injection monthly for 6 months then every alternate month throughout the study. The primary endpoint was the rate of decline in CD4 count; secondary endpoints were HIV-1 RNA concentrations in plasma and minor clinical events associated with HIV. Analysis was by intention to treat. FINDINGS: At baseline, the study participants had a mean CD4 count of 775 cells/microL (SD 172) and 89% of participants had detectable HIV RNA (> 200 copies/mL). These RNA-positive individuals had a median viral load of 9250 copies/mL (IQR 2670-26960). Analysis after 15 months of follow-up of the 568 subjects who had at least one CD4 count done after randomisation showed no difference between the 287 vaccine recipients and 281 placebo recipients in rate of decline of CD4 count (yearly decrease 53.8 [SE 7.6] vs 42.3 [7.6] cells/microL; ratio of mean gradients 1.27 [95% CI 0.63-2.55]) or in plasma HIV-1 RNA concentrations (p > or = 0.63). The study was designed with power to detect a vaccine-induced reduction in rate of decline in CD4 count of 60%; these results exclude with 95% confidence a reduction of 40% or more. More vaccine-treated patients than placebo recipients showed a 50% decrease in CD4 count (11 vs 5; relative risk 2.15 [95% CI 0.76-6.12], p = 0.13). The frequencies of HIV-related minor clinical events were similar in the two groups. Pain at the injection site was the only adverse event that occurred more frequently in vaccine-treated group. INTERPRETATION: Postinfection immunisation of symptom-free HIV-infected patients with MNrgp120 vaccine did not alter HIV-1 disease progression as measured by immunological, virological, and clinical endpoints over a 15-month period.

Psychosocial support, treatment of metastatic disease and palliative care.

This article deals with four linked but distinct aspects of care for women with breast cancer, with an emphasis on the pivotal role of the general practitioner: 1. Modern medicine is fast recognising the need for psychosocial support of patients; in fact, for an integrated approach to caring for the whole person at all stages of illness. 2. Oncological treatment of metastatic disease needs to be individualised and based on realistic expectations of outcome balanced against side effects. 3. An open dialogue about the role and appropriateness of so-called "alternative" or "complementary" therapies is needed. 4. Despite significant improvements in palliative care quality and access in Australia in the last decade, many practitioners still require support and advice in this demanding area of care (particularly about difficult symptom control).

General practitioners and palliative care.

A randomly selected sample of 158 South Australian general practitioners (GPs) were sent a questionnaire which assessed opinions and management practices in the palliative care of terminally ill patients. A total of 117 responses (74%) were received. Most GPs were at least moderately satisfied with the care they were able to give their terminally ill patients, although a substantial number reported difficulties in pain and other symptom control, dealing with relatives' emotional distress and attending to patients' psychosocial needs. There was considerable support for continuing education in these aspects of palliative care. More than half were at least somewhat concerned by opioid side effects and impairment of cognitive function, although opioid dependence was not a concern. Considerable dissatisfaction was expressed with public hospital care for the terminally ill and most felt excluded from decision-making once their patients were admitted. The findings suggest that continuing education is required for GPs and that palliative care should become an integral part of undergraduate education. There is also a need to enhance communication and co-ordination between hospital and community-based services for the terminally ill.

An enquiry into death and dying at the Adelaide Children's Hospital: a useful model?

As a result of a desire amongst the hospital staff to improve the management of dying children and their families, a four person subcommittee was appointed to investigate this area of care. Nineteen persons were interviewed (15 hospital staff members and four parents) and 12 written submissions were received (10 from staff and two from parents) over a 10 week period. An analysis of one year's deaths of Adelaide Children's Hospital patients showed that most took place in the hospital and about one in five were at home. Nearly 60% occurred in children aged 0-5 years, 15% in those aged 6-10 years, 15% in those aged 11-15 years, and 13% in children aged more than 15 years. The four commonest causes of death were: cancer (27%), congenital abnormalities (19%), sudden infant death syndrome (SIDS) (16%), and trauma (11%). Sudden unexpected deaths are most common, particularly for infants. Recommendations included improved privacy for families and friends; more sensitive body viewing, mortuary, autopsy and funeral arrangements; and better in-service education for staff and information giving for families. Areas of insufficient staff support were identified and the appointment of a specialist palliative care clinical nurse consultant was proposed. Stronger links with palliative and hospice care teams, general practitioners and community nurses were suggested. Addressing the issues of living and dying, and working through the stages of grief are integral parts of long term clinical care. The need for good continuity of psychosocial support was a recurring theme. More awareness of the availability of the specialised pain relief service was required. Ethical issues should be addressed as part of the general development of education and information services. The advantages and limitations of the enquiry are discussed and the model is proposed as a potentially useful one for both paediatric and adult palliative care and hospice care service development.

Treatment of non-melanoma skin cancer: a review of recent trends with special reference to the Australian scene.

Non-melanoma skin cancer (NMSC) is rarely recorded in cancer registries and it is only relatively recently that the serious public health implications, especially in terms of morbidity and expense, have been appreciated. Increased recreational sun exposure (particularly among the young) and ozone layer depletion have generated concern in many countries. Histological confirmation of the diagnosis, either by excision biopsy or punch biopsy is essential if management of the condition is to be rational and the results assessed. Surgery or radiotherapy or other dermatological techniques will cure over 90% of all NMSC. Comparison of the results of various modalities is difficult and poorly documented. Local recurrence rates of 2.0% for surgery and 3.7% for superficial X-ray treatment (SXRT), with 96% and 90% 5-year failure-free-survival respectively are reported from the Peter MacCallum Cancer Institute. More comparative trials are required with good cosmetic and late normal tissue damage evaluation. Factors affecting modality choice trends in Australia are discussed, where the role of plastic surgery has considerably expanded. The indications for radiotherapy and its fractionation require clarification, as does the use of moulds and implants. The belief that solar keratoses transform to invasive cancer has been seriously brought into question by recent Australian epidemiological studies. There can, however, be little doubt of the fact that keratoses are markers of cumulative solar damage, which is a well recognised risk factor for development of NMSC. There is a move away from aggressive ablative treatment of keratoses. The management of keratoacanthoma (KA) by observation is the usual practice, although radiotherapy is occasionally used when the lesion is conspicuous and unsightly.(ABSTRACT TRUNCATED AT 250 WORDS)

Presentation of axillary lymphadenopathy without detectable breast primary (T0 N1b breast cancer): experience at Institut Curie.

Between 1960 and 1985, 31 patients presented to Institut Curie with isolated axillary lymphadenopathy, of probable metastatic origin from the breast, but without clinical or radiological evidence of a breast tumor and no other primary tumor. The mean age was 54.6 years (range 39-79 years). Histological diagnosis was obtained by axillary surgery (22 cases), drill biopsy (6 cases), and cytology (3 cases). All slides were reviewed for the present study. Treatment consisted of axillary surgery followed by radiotherapy in 22 patients, radiotherapy followed by axillary surgery in 6 patients, radiotherapy followed by modified radical mastectomy in one patient, and radiotherapy alone in 2 patients. Systemic adjuvant treatment was given to 11/31 patients. The median follow-up was 9 years (range 2-26 years). Eight recurrences have appeared. Four patients recurred in the breast only (mean time to relapse: 112 months, range 63-162 months). The four other patients recurred both in breast and/or axilla (mean time to relapse: 23 months, range 7-46 months). Nine patients have developed distant metastases, of whom three also had locoregional recurrence. Among the 11 patients who had had systemic treatment, 5/11 had recurrence or metastases. The overall 5 and 10 year actuarial survival rates were 76 and 71%, respectively. The metastasis-free 5 and 10 year actuarial survival rates were 73 and 71%, respectively. Axillary metastases without clinical or radiological evidence of a primary breast tumor represents a discrete clinical entity, the prognosis of which appears to be better than that of clinical invasive breast cancer with associated lymph node involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of a radon mould technique for skin cancer: results from the Peter MacCallum Cancer Institute (1975-1984).

During the period from 1975 to 1984, 642 patients had non-melanoma skin cancers (NMSC) treated by a radon mould technique following the principles of the Manchester system. The results of 77 out of 642 (12%) with histologically verified lesions are presented. The sites of the lesions were as follows: head and neck 25 (32%), upper limbs 38 (49%), lower limbs 13 (17%) and trunk one case only. The histological diagnosis was squamous cell carcinoma 48 (62%), basal cell carcinoma in 22 (29%) and other in seven (9%). There were nine out of 77 (12%) failures, four with persistent disease, which did not clear after initial treatment (and for whom the radon mould was an inappropriate choice of technique), and five (6%) recurrences after clearance of the initial lesion. There was a sharp rise in failures after 1979 when there was a change of radon supplier, but no calibration error was substantiated. It is clearly beneficial for institutions to cross-check the manufacturer's brachytherapy source data. There have been no further recurrences or any symptomatic late morbidity. This is a safe, effective and practical radiotherapeutic technique for superficial lesions (not exceeding a depth of 4 mm) in areas of poor radiation tolerance, and may obviate the need for a prolonged fractionated course of external-beam radiation in selected patients. Alternatives to radon are discussed.

Treatment of nonmelanoma skin cancer at a large Australian center.

One thousand one hundred fifty-four cases of nonmelanoma skin cancer (NMSC) referred to the Consultative Skin Clinic at Peter MacCallum Cancer Institute (PMCI) (Melbourne, Australia) in 1980 were reviewed. The median age was 68 years, and the male to female ratio was 1.5:1. Final diagnosis was basal cell carcinoma (BCC) in 901 patients (78%), squamous cell carcinoma (SCC) in 242 patients (21%), and basosquamous carcinoma in 11 patients (1%). Seven hundred twelve (62%) were biopsy proven. Comparison of clinical and histologic diagnoses showed that BCC were correctly diagnosed clinically in 85% of cases but only 53% of SCC were correctly diagnosed. The distribution of sites was as follows: head and neck 871 (75%), limbs 131 (11%), trunk 50 (4%), and multiple sites 102 (9%). One thousand eighty-nine (94%) had primary lesions and 65 (6%) had recurrent lesions. The lesions were treated with surgery in 55% of cases, superficial radiotherapy in 39%, other types of radiotherapy in 3%, cryotherapy in 1%, and 5-fluorouracil in 0.2%. Recurrent lesions, lesions on the eyelids, ears or nose, and T4 lesions were significantly associated with increased failure rates. Superficial radiotherapy was associated with a 2.3-fold increase in failure rate compared to surgery when other prognostic factors were taken into account (P = 0.01, 95% confidence interval = 1.2-4.3). Nonsuperficial radiotherapy was associated with an 11.5-fold increase in failure rate compared to surgery (P less than 0.0001, 95% confidence interval = 4.9-27.1), but several of these cases were treated for palliative purposes only. The results of, and indications for treatment with surgery or radiotherapy at PMCI are discussed.

Primary cutaneous neuroendocrine (Merkel cell or trabecular carcinoma) tumour of the skin: a radioresponsive tumour.

Four patients with primary neuroendocrine carcinoma of the skin (Merkel cell or trabecular carcinoma) are reported to document their response to radiotheraphy. In three patients there was complete response following radiation treatment, with no local recurrence, whilst the other patient died later with distant metastases. In one patient, post-operative irradiation after excision of an involved local node prevented the growth of further tumour in this nodal group but the unirradiated primary site recurred after initial wide local excision only. This rare tumour appears to be radioresponsive, and although more clinical data are required, we would advocate a wider study of radiotherapy to the primary lesion after biopsy or excision biopsy, in association with prophylactic nodal irradiation. These tumours occur predominantly in elderly people in whom the avoidance of extensive surgery is particularly desirable.