Palliative sedation therapy does not hasten death: results from a prospective multicenter study.

BACKGROUND: Palliative sedation therapy (PST) is indicated for and used to control refractory symptoms in cancer patients undergoing palliative care. We aimed to evaluate whether PST has a detrimental effect on survival in terminally ill patients. METHODS: This multicenter, observational, prospective, nonrandomized population-based study evaluated overall survival in two cohorts of hospice patients, one submitted to palliative sedation (A) and the other managed as per routine hospice practice (B). Cohorts were matched for age class, gender, reason for hospice admission, and Karnofsky performance status. RESULTS: Of the 518 patients enrolled, 267 formed cohort A and 251 cohort B. In total, 25.1% of patients admitted to the participating hospices received PST. Mean and median duration of sedation was 4 (standard deviation 6.0) and 2 days (range 0-43), respectively. Median survival of arm A was 12 days [90% confidence interval (CI) 10-14], while that of arm B was 9 days (90% CI 8-10) (log rank = 0.95, P = 0.330) (unadjusted hazard ratio = 0.92, 90% CI 0.80-1.06). CONCLUSION: PST does not shorten life when used to relieve refractory symptoms and does not need the doctrine of double effect to justify its use from an ethical point of view.

Heterogeneous protooncogene amplification correlates with tumor progression and presence of metastases in gastric cancer patients.

In order to evaluate the relevance of protooncogene alterations in gastric cancer and to specifically relate these alterations to types and stages of the neoplasia, we studied oncogenes of possible interest in gastric tumors with different clinical parameters. Fifty DNAs from primary gastric adenocarcinoma were analyzed, by the Southern blotting technique, for the presence of amplification or rearrangements of seven different protooncogenes: c-myc, c-erbB2, c-Ki-ras, c-Ha-ras, c-N-ras, hst, and c-mos. All the tumors analyzed were histologically classified and staged. Amplification of the following genes was found: c-myc (2 of 50), hst (3 of 50), c-erbB2 (3 of 50), and c-Ki-ras (5 of 50). The simultaneous amplification of hst (3 cases), c-myc (1 of 3), or c-Ki-ras (2 of 3) was observed. Analysis of DNAs from atrophic and metaplastic gastric mucosa (which can be regarded as preneoplastic lesions) of the 10 patients showing gene amplification demonstrated that this was limited to neoplastic cells. Considering protooncogene amplification in general (i.e., involving different genes and occurring to different degrees) and clinical parameters of tumors, we found a statistically significant association between amplification and both tumor progression and presence of metastases. Therefore, at least for the genes analyzed, amplification is a relatively infrequent phenomenon and represents a late event in the temporal development of gastric cancer.

Palliative care in advanced cancer.

Palliative care represents a new field among clinical approaches to patients with advanced or terminal cancer. The modern concept of palliative care can be considered in several ways: 1) the relationship between palliative care and primary treatments of cancer (surgery, radiotherapy or chemotherapy); 2) the treatment of symptoms and the relationship between symptom control and quality of life; 3) end-of-life care. With regard to the relationship between palliative care and primary cancer treatments, it is common opinion that a continuity of care is needed from diagnosis to the terminal phase of the disease, and oncology departments could represent the ideal dimension in which to fulfil this requirement. In a continuity-of-care setting, symptom control becomes vitally important to improve quality of life of the patient throughout all the stages of the disease. Moreover, support for the patient and his/her family during the terminal phase of the disease is one of the most important dimensions of palliative care. In addition, assistance provided during the last hours of life and support for the family after the patient's death represent the so-called global assistance, which is distinctive of palliative care.

Clinical and laboratory evaluation of the myeloprotective effect of medroxyprogesterone acetate in head and neck cancer.

The action of high-dose medroxyprogesterone acetate (MPA) was studied by analysing the behaviour of colony-forming-unit granulocyte-macrophage (CFU-GM) during chemotherapy. 21 non-pretreated men with locally advanced carcinoma of the head and neck were randomised into two arms: A (11 patients) received three alternating cycles of cisplatin, 5-fluorouracil (CF)/cisplatin, methotrexate, bleomycin, vincristine and then CF every 4 weeks and B (10 patients) were treated with the same schedule plus 1000 mg per day of MPA. MPA was administered 14 days before the start of chemotherapy (day 0) and continued daily up to the 90th day. Bone marrow was harvested in arm A on days 0, +14 and +90, and in B, also on day -14. There was diverse CFU-GM behaviour in the two arms on the 14th day. These data support the hypothesis that the myeloprotective effect of MPA is due to induction of a mitotic rest in the stem cells, which protects them from drug action.

Clinical prediction of survival is more accurate than the Karnofsky performance status in estimating life span of terminally ill cancer patients.

Predicting the survival of terminally ill cancer patients can help in informing patients and their families, in programming therapy and assistance models, and in utilising existing resources correctly. Clinical prediction of survival (CPS) and Karnofsky performance status (KPS) are two factors which have already been described in the literature. The aim of our study was to verify their respective predictive value with regard to actual survival. In our study of 100 consecutive patients, the CPS obtained a higher prediction accuracy than that reported previously (correlation coefficient with actual survival = 0.51) and than that obtained with KPS alone (correlation coefficient = 0.37). The median difference between predicted and expected survival was only 1 week. The resultant predictivity could be further improved by integrating other prognostic factors studied in larger prospective, multicentric studies.

Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation.

In late 1990, it became standard practice at the palliative care unit of the Edmonton General Hospital to regularly administer the Mini-Mental State Questionnaire (MMSQ) and to undertake opioid rotation and hydration upon detection of cognitive failure. We retrospectively reviewed the charts of 117 and 162 patients admitted in 1988-1989 and 1991-1992, respectively, to assess the impact of these maneuvers on the prevalence of agitated impaired mental status (IMS). All patients underwent regular cognitive assessment in 1991-1992 versus none in 1988-1989. Seventy-three percent of patients received hydration in the second period versus 32% in the first (P < 0.01). The frequency of opioid rotation was also greater in the second period (41% versus 21%, P < 0.001). The incidence of agitated IMS decreased from 26% in 1988-1989 to 10% in 1991-1992 (P < 0.001). This was reflected by a lower mean dose of the major drug used to treat this condition, haloperidol (3.6 +/- 2.4 versus 5.6 +/- 3.8 mg/day, P < 0.01), and less frequent use of other neuroleptics and benzodiazepines (0.12 versus 0.38 prescriptions per patient, P < 0.01) in the second period. Our data suggest that routine cognitive monitoring, opioid rotation, and hydration may reduce the incidence of agitated IMS in terminal cancer patients.

Biological indices predictive of survival in 519 Italian terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care.

The knowledge of prognostic factors capable of subdividing cancer patients into groups having homogenous survival times is useful even in very advanced stages of illness. This prospective multicenter study assessed these prognostic factors in 530 terminal patients with solid tumors who were undergoing only palliative care. Thirteen hematological and urinary parameters were assessed on admission and every 28 days thereafter. In 519 assessable patients with a median survival of 32 days, six biological parameters demonstrated a statistically significant predictive prognosis. A poor prognosis was predicted by high total white blood count (WBC) (P < 0.0001), high neutrophil percentage (P < 0.0001), low lymphocyte percentage (P < 0.0001), low serum albumin level (P = 0.0015), low pseudocholinesterase level (P < 0.0001), and high proteinuria (P = 0.0064). Multiple regression analysis showed that only WBC, lymphocyte percentage and pseudocholinesterase level were independent predictors of survival. The individualization of biological parameters having an independent prognostic capacity is a useful step in the attempt to identify subsets of patients with a homogeneous prognosis. The biological factors needed are easily detected by means of a simple blood test and do not require invasive operations on patients who are already debilitated.

Assessing delirium in cancer patients: the Italian versions of the Delirium Rating Scale and the Memorial Delirium Assessment Scale.

To validate the Italian versions of the Delirium Rating Scale (DRS) and the Memorial Delirium Assessment Scale (MDAS), 105 cancer patients consecutively referred for neurological or psychiatric consultation for mental status change were evaluated using the Confusion Assessment Method (CAM), the DRS, the MDAS, and the Mini-Mental State Examination (MMSE). According to the CAM criteria and clinical examination, 66 patients were delirious, and 39 received diagnoses other than delirium. The DRS and the MDAS scores significantly distinguished delirious from non-delirious patients. The MDAS and the DRS were mutually correlated. When using the proposed cut-off scores for the two scales, the MDAS had higher specificity (94%) but lower sensitivity (68%) than the DRS (sensitivity = 95%, specificity = 61% for DRS cut-off 10; sensitivity = 80%, specificity = 76%, DRS cut-off 12). The MMSE showed high sensitivity (96%) and very low specificity (38%). Exploratory factor analysis of the DRS and the MDAS suggested a three-factor and two-factor structure, respectively. Both instruments in their Italian version proved to be useful for the assessment of delirium among cancer patients. Further research is needed to examine the use of the DRS and the MDAS in other clinical contexts.

A new palliative prognostic score: a first step for the staging of terminally ill cancer patients. Italian Multicenter and Study Group on Palliative Care.

In recent years, extensive research has been performed to identify prognostic factors that predict survival in terminally ill cancer patients. This study describes the construction of a simple prognostic score based on factors identified in a prospective multicenter study of 519 patients with a median survival of 32 days. An exponential multiple regression model was adopted to evaluate the joint effect of some clinico-biological variables on survival. From an initial model containing 36 variables, a final parsimonious model was obtained by means of a backward selection procedure. The Palliative Prognostic Score (PaP Score) is based on the final model and includes the following variables: Clinical Prediction of Survival (CPS), Karnofsky Performance Status (KPS), anorexia, dyspnea, total white blood count (WBC) and lymphocyte percentage. A numerical score was given to each variable, based on the relative weight of the independent prognostic significance shown by each single category in the multivariate analysis. The sum of the single scores gives the overall PaP Score for each patient and was used to subdivide the study population into three groups, each with a different probability of survival at 30 days: (1) group A: probability of survival at 30 days > 70%, with patient score < or = 5.5; (2) group B: probability of survival at 30 days 30-70%, with patient score 5.6-11.0; and (3) group C: probability of survival at 30 days < 30%, with patient score > 11.0. Using this method, 178/519 (34.3%) patients were classified in risk group A, 205 (39.5%) patients were in risk group B, and 136 (26.2%) patients were in risk group C. The patients classified in the three risk groups had a very different survival experience (logrank = 294.8, P < 0.001), with a median survival of 64 days for group A, 32 days for group B, and 11 days for group C. The PaP Score based on simple clinical and biohumoral variables proved to be statistically significant in a multivariate analysis. The score is valid in this population (training set). An independent validation on another patient series (testing set) is required and is the object of a companion paper.

Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care.

The aim of this work was to validate a previously constructed prognostic score for terminally ill cancer patients in order to determine its value in clinical practice. The Palliative Prognostic Score (PaP Score) was tested on a population of 451 evaluable patients consecutively entered in the hospice programs of 14 Italian Palliative Care Centers. The score subdivided patients into three specific risk classes based on the following six predictive factors of death: dyspnea, anorexia, Karnofsky Performance Status (KPS), Clinical Prediction of Survival (CPS), total white blood count (WBC), and lymphocyte percentage. The performance of the PaP Score index in the training and testing sets was evaluated by comparing mortality rates in the 3 prognostic risk categories. The score was able to subdivide the validation-independent case series into three risk groups. Median survival was 76 days in group A (with a 86.6% probability of 30-day survival), 32 days in group B (with a 51.6% probability of 30-day survival), and 14 days in group C (with a 16.9% probability of 30-day survival). Survival medians were remarkably similar to those of the training set (64 days in group A, 32 days in group B, and 11 days in group C). In the complex process of staging terminally ill patients, the PaP Score is a simple instrument which permits a more accurate quantification of expected survival. It has been validated on an independent case series and is thus suitable for use in clinical practice.

Topical prostaglandin E2 and chemo- and radio-induced oral mucositis.

Oral mucositis is a frequent complication of specific antineoplastic treatments. Mouth lesions have a great impact on the quality of life of cancer patients. Current topical and systemic therapies have not yet achieved completely satisfactory results. We studied the effect of topical use of prostaglandin E2 (PGE2) 2.25 mg/day on oral mucositis of 15 chemo- or radio-treated cancer patients. Absolute mean VAS value on mouth pain decreased from 71.2 at TO, to 34.1 at T3 (p<0.001) and to 14.1 at T6 (p<0.001). Objective evaluation according to Miller scale showed significant improvement at day 3 and 6, as well. We suggest that PGE2 could be a useful additional therapeutic agent to palliate oral symptoms.

Description of a home care service for cancer patients through quantitative indexes of evaluation.

Home care (HC) was created and developed in Romagna, as in other parts of Italy, thanks to the endeavor of a private institution, the "Istituto Oncologico Romagnolo". The care is gratis to advanced cancer patients and is based on the palliative philosophy of treatment of the symptoms and the person within the framework of continuity of care permitted by the oncologic approach. To evaluate the intensiveness of the operation in terms of medical and nursing care by means of quantitative indexes, we examined several variables which emerged from a retrospective analysis of our case study. The average duration of care of the 484 patients in the program as of 31 December 1990 was 84.1 days. Four hundred and twenty-three patients of the 484 (87.1% of the total) have died and 61 were still in the HC program at the time of this analysis. The 61 living patients were thus excluded from the descriptive analysis to give greater homogeneity to the study group. The average duration of care for the 423 decreased patients was 68.1 days. Out of a total of 28,759 days of HC for the entire group, the patients actually spent 23,534 days (81.8%) at home. The average duration of hospitalization was 13.5 days, and in 33.2% of the cases it was motivated by psychologic and family causes. The place of death was the home in 44.3% of the cases. A medical or nursing visit was made at the home every 1.4 days, and the average number of visits per patient was 39.0. Although none of the indexes alone can give overall indications of the intensiveness of a HC service, they may constitute a working proposal for the definition of the most objective criteria possible for the quantitative evaluation of such experiences.

A retrospective study of FAM regimen in 38 patients with advanced gastric cancer.

Gastric carcinoma has a very poor prognosis, with a survival rate at 5 years of 13%. Various chemotherapy regimens have been used in the advanced stages of the disease. The best results were obtained using the FAM combination. We treated 38 patients with advanced measurable gastric cancer using the FAM combination and obtained 23.67% complete plus partial remission (CR + PR) (32% with more restrictive criteria for eligible patients) and 34% no change. The median length of response was 30 weeks in CR patients (range 20-100) and 26 weeks (range 12-34) in PR patients. Responsive patients (CR + PR) had a median survival of 12.3 months (range 5-22) compared to nearly 4 months (range 2-8) for unresponsive patients.

Primary lymphoma of the central nervous system.

Primary lymphoma of the central nervous system (CNS) represents a pathology that is no longer considered rare, also in the light of its high correlation with the human immunodeficiency virus (HIV) syndrome reported recently. Often the correct diagnosis of the disease is difficult to reach, owing to the wide spectrum of non-lymphoma pathologies from which it should be differentiated and the invasiveness of some diagnostic techniques. The biologic aggressiveness of the neoplasm often makes a combined radio-chemotherapeutic approach necessary. In contrast, surgical resection does not seem to provide any significant benefit. The clinical experience reported here, together with a review of the most recent literature, lead the authors to suggest the opportunity of treating primary lymphoma of the CNS with the most active and modern chemotherapeutic protocols in association with traditional treatments to obtain an improvement in overall survival.

Combination chemotherapy in advanced ovarian carcinoma.

Ovarian carcinoma is the fifth most common cause of death among women in western countries. It is often diagnosed in an advanced stage (FIGO Stage III and IV) and requires effective chemotherapy as first-line treatment. The advent of cis-platin combined with adriamycin and cyclophosphamide has remarkably increased the response rate in advanced disease. The authors report 31 cases of epithelial ovarian neoplasia, without prior chemotherapy, treated with cis-platin, adriamycin and cyclophosphamide (PAC I). Of the 30 evaluable patients, 15 had clinical complete remissions (cCR = 50%), 10 clinical partial remissions (cPR = 33%) and 5 no response (NR = 17%). The total response (cCR + cPR) was equal to 83%. Twelve of the 15 patients in cCR underwent second-look laparotomy; in 8 of these cases, histologic and cytologic confirmation of CR was obtained. PAC I was found to be a highly effective therapeutic regimen with moderate toxicity. The individual toxicity reported was gastroenteric (nausea and vomiting), but transitory. No chronic toxic side-effects from cisplatin or adriamycin were noted. However, more definitive results must be obtained to verify its impact on the prolongation of survival.

Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients.

Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed.