Are strong opioids equally effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV 'real life' trial on the variability of response to opioids.

BACKGROUND: Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in the treatment of chronic cancer pain, but individual responses can vary. This study compared the analgesic efficacy, changes of therapy and safety profile over time of four strong opioids given for cancer pain. PATIENT AND METHODS: In this four-arm multicenter, randomized, comparative, of superiority, phase IV trial, oncological patients with moderate to severe pain requiring WHO step III opioids were randomly assigned to receive oral morphine or oxycodone or transdermal fentanyl or buprenorphine for 28 days. At each visit, pain intensity, modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy end point was the proportion of nonresponders, meaning patients with worse or unchanged average pain intensity (API) between the first and last visit, measured on a 0-10 numerical rating scale. (NCT01809106). RESULTS: Forty-four centers participated in the trial and recruited 520 patients. Worst pain intensity and API decreased over 4 weeks with no significant differences between drugs. Nonresponders ranged from 11.5% (morphine) to 14.4% (buprenorphine). Appreciable changes were made in the treatment schedules over time. Each group required increases in the daily dose, from 32.7% (morphine) to 121.2% (transdermal fentanyl). Patients requiring adjuvant analgesics ranged from 68.9% (morphine) to 81.6% (oxycodone), switches varied from 22.1% (morphine) to 12% (oxycodone), discontinuation of treatment from 27% ( morphine) to 14.5% (fentanyl). ADRs were similar except for effects on the nervous system, which significantly prevailed with morphine. CONCLUSION: The main findings were the similarity in pain control, response rates and main adverse reactions among opioids. Changes in therapy schedules were notable over time. A considerable proportion of patients were nonresponders or poor responders. CLINICAL TRIAL REGISTRATION: NCT01809106 (https://clinicaltrials.gov/ct2/show/NCT01809106?term=cerp&rank=2).

Impact of early access to a palliative/supportive care intervention on pain management in patients with cancer.

BACKGROUND: No study has so far addressed whether differences do exist in the management of cancer pain between patients receiving usual care by primary specialists and those receiving early palliative/supportive intervention. PATIENTS AND METHODS: A multicentre cross-sectional study in 32 Italian Hospitals has included 1450 patients, receiving analgesic therapy for cancer pain: 602 with access to primary specialist alone (standard care, SC) and 848 with early access to a palliative/supportive care (ePSC) team, concomitant with primary oncology care. RESULTS: Statistically significant differences in the analgesic drug administration according to care model have been evident: non-opioids were more frequently used in SC (9.5% versus 2%; P<0.001), while strong opioids in ePSC group (80% versus 63%; P<0.001). The number of patients with severe pain was lower in ePSC compared with SC group (31% versus 17%; P<0.001). Results of multivariate analysis have shown that ePSC integrated with primary oncologic care (relative risk 0.69; 95% confidence interval 0.48-0.99; P=0.045) was an independent factor associated with a 31% reduced risk of suffering from severe pain. CONCLUSIONS: An ePSC team provides the most effective standard of analgesic therapy for cancer pain. A randomized clinical trial is needed to confirm these findings.

Updating clinical recommendations for breast, colorectal and lung cancer treatments: an opportunity to improve methodology and clinical relevance.

BACKGROUND: clinical guidelines can improve quality of care summarising available knowledge and proposing recommendations for health care decisions. Being up to date is one of their quality requisites. Little experience is available on when and how guidelines should be updated. We report on the update process of evidence-based clinical recommendations on anticancer drugs. METHODS: three multidisciplinary panels, supported by methodology experts, updated the recommendations. The methodologists were in charge of the qualitative and quantitative synthesis of the evidence. The panels were responsible for the final decision about risk/benefit profile of the drugs and strength of the recommendations. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used. RESULTS: six recommendations out of 15 were completely updated in 8 months time. In four cases, the strength of the recommendation changed; in two of them, we moved from a weak to a strong positive one. Despite the increased certainty about the positive risk/benefit profile, this was translated in a change in the strength of the recommendation only in one case out of three. Three recommendations were refined making them more clinically specific. CONCLUSIONS: accumulation of evidence is an opportunity for guideline panels to refine methodological rigour, clinical relevance and to foster consensus on recommendations. This requires time and resource investments.

Impact of setting of care on pain management in patients with cancer: a multicentre cross-sectional study.

BACKGROUND: No study has so far addressed whether differences do exist in the management of cancer-related pain in patients admitted to oncology and non-oncology settings. PATIENTS AND METHODS: A multicentre cross-sectional study in 48 Italian hospitals has enrolled 819 patients receiving analgesic therapy for cancer-related pain. Demographics and clinical and analgesic therapy information have been prospectively collected by standardized forms. Adequacy of pain management has been evaluated by the Pain Management Index (PMI). RESULTS: Differences in the analgesic drug administration according to settings of care have been evident, non-opioids more frequently being administered in non-oncology units (19.6% versus 7.0%; P < 0.0001), while strong opioids are more frequently used in the oncology units (69.5% versus 51.9%; P < 0.0001). The number of patients receiving inadequate therapy (PMI < 0) has lowered in oncology compared with non-oncology units (11.3% versus 18.8%; P = 0.0024). Results of multiple logistic regression analysis have shown that the admission to non-oncology setting [odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.15-2.67; P = 0.0096] and the absence of metastatic disease (OR = 1.60, 95% CI = 1.04-2.44; P = 0.0317) were independent factors associated with an increased risk of receiving an inadequate analgesic therapy. CONCLUSION: Oncology wards provide the most adequate standard of analgesic therapy for cancer-related pain.

Use of oxycodone controlled-release immediately after NSAIDs: a new approach to obtain good pain control.

INTRODUCTION: Opioids are recommended as appropriate therapy for the treatment of cancer pain and chronic non-malignant pain. Oxycodone is an alternative agent to its parent compound, morphine, and is available in a controlled-release (CR) formulation that allows convenient twice-daily dosing. The aim of this study was to evaluate the efficacy and tolerability of oxycodone CR as first-line therapy in patients with chronic cancer or non-cancer pain that was not relieved by non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: This was a prospective, open-label, multicentre trial carried out in 8 pain and oncology centres in Italy. Patients (n = 309) with NSAID-refractory chronic cancer (55.7%), noncancer (39.4%) or mixed (4.9%) pain (rating of 4-10 on a numerical rating scale [NRS] from 0-10) were enrolled. Patients were treated with oral oxycodone CR twice daily for at least 28 days. Dosage was individualized for each patient and up-titrated over the first week of treatment. The primary endpoint was reduction in NRS score for pain. Secondary endpoints were tolerability, quality of life and patient assessment of treatment efficacy. RESULTS: A significant decrease (57%) in pain intensity was recorded during the first week of therapy (decrease in NRS score from 7.85 +/- 1.4 to 3.35 +/- 1.8; p < 0.00001). Overall, there was a 72.3% reduction in NRS pain score from baseline at the end of the study. Quality of life significantly (p < 0.005) improved during oxycodone therapy, and 91% of patients rated treatment as "effective" or "very effective". Five patients stopped oxycodone CR treatment because of adverse events, and one stopped treatment because of dysphagia. CONCLUSIONS: The results of this study demonstrate the efficacy and tolerability of oxycodone CR in patients with moderate-to-severe pain of a variety of aetiologies and confirm the feasibility and effectiveness of moving directly from step I to step III on the WHO analgesic treatment ladder.

Lepidium meyenii Walp. improves sexual behaviour in male rats independently from its action on spontaneous locomotor activity.

Lepidium meyenii Walpers (Maca) is traditionally employed in the Andean region for its supposed properties to improve energy and fertility. The aim of this study was to evaluate the effect of acute and chronic Maca pulverised root oral administration on rat sexual behaviour. Sixty male sexually experienced rats (20 group) were daily treated for 15 days with Maca 15 mg kg(-1), Maca 75 mg kg(-1) or saline 0.5 ml kg(-1). The following sexual performance parameters were evaluated at first and last day of treatment: 1st mount (ML), 1st intromission (IL), ejaculation (EL) and postejaculatory (PEL) latencies, intercopulatory interval (ICI) and copulatory efficacy (CE). An activity cage test was carried out to evaluate if Maca-induced locomotion changes could indirectly improve rat sexual performances. It was observed that both lower and higher Maca doses acutely decreased ML, IL and ICI in a significant way (P < 0.05), while only the 75 mg kg(-1) dose decreased the PEL (T = 29, P < 0.05). This effect seems to be the only one dose-dependent. After 15 days of treatment, both doses are able to significantly decrease ML, IL, EL and PEL, while the 75 mg kg(-1) dose decreased the ICI (T = 40, P < 0.05) too. IL, EL and PEL variations seem to be dose-related after chronic treatment. Moreover, chronic Maca treatment induced an apparently not dose-related increase in rat locomotion, during the second 10-min period of observation in the activity cage. The late in Maca-induced locomotion modification excludes that improvement of tested sexual performance parameters is related to an increase in rat aspecific activity. Thus, it was concluded that both acute and chronic Maca oral administration significantly improve sexual performance parameters in male rats.

Prospective phase II study of single-agent gemcitabine in untreated elderly patients with stage IIIB/IV non-small-cell lung cancer.

The purpose of this study was to evaluate the efficacy and tolerability of single-agent gemcitabine in untreated elderly patients with stage IIIb/IV non-small-cell lung cancer (NSCLC). Since April 1997, 46 consecutive patients have been enrolled in this multicenter study. Gemcitabine 1,000 mg/m2 was administered as a 30-minute intravenous infusion on days 1, 8, and 15 every 28 days. Primary patient characteristics were: male/female 38/8; median age 73 years (range: 70-82 years); median Karnofsky performance status (PS) 90 (range: 70-100); stage IIIb 61% and stage IV 39%; histotype: epidermoid 48%, adenocarcinoma 43%, and large cell carcinoma 9%. No complete response was observed, but 10 (21.7%) patients achieved partial response (PR) (95% confidence limits: 11-36%), 27 (58.7%) had stable disease (SD), and 7 (15%) progressed early (at the first evaluation). The median duration of PR and SD was 8 months (range: 4-23+ months) and 4 months (range: 2-9 months), respectively. Subjective response evaluating PS and symptoms such as dyspnea, pain, and cough was evaluated in 40 patients; 11 (27.5%) improved, 15 (37.5%) remained stable, and 14 (35%) worsened. The median time to progression was 4 months, the median survival was 9 months, and 1-year survival was 44%. After a median follow-up of 10.5 months, 14 patients are still alive. There were no grade 4 toxicities. Grade 3 neutropenia and thrombocytopenia occurred in 19% and 2% of patients, respectively. Nonhematologic toxicities were mild. Grade I/II side effects of nausea/vomiting, transient fever, increase of hepatic transaminases, transient peripheral edema at lower extremity (not related to cardiac or renal disease or phlebothrombosis) were reported. This phase II study confirms the activity and favorable toxicity profile of single-agent gemcitabine in the treatment of elderly patients with advanced NSCLC.

Orally administered Panax notoginseng influence on rat spontaneous behaviour.

Panax notoginseng root is highly prized in China for its supposed hemorheological properties. Its behavioural effects are still not scientifically investigated; therefore, our preliminary study aim is to evaluate the influence of this phyto-drug on rats spontaneous behaviour. High quality P. notoginseng root dry extract has been orally administered through gastric tube for 10 days in two doses (43 and 86 mg/kg in a volume of 5 ml/kg per day) and its effects on locomotion, emotional reactivity and nutrition have been evaluated in different groups of Wistar rats (ten per group) versus animals treated with 5 ml/kg per day of saline. Actimeter test, open field test and microstructural analysis of unconditioned behaviour were carried out. The data were processed by ANOVA-test followed by the Student's one-tail t-test and a 0.05 significance level was chosen for all statistical tests. A significant increase in spontaneous motility being not associated to an increase in grooming episodes duration and number was found in all tests (P<0.05). Feeding behaviour appeared not to be affected by the treatment. Observed effects did not seem dose-related. Reduction of grooming episodes duration and number and increase of inner crossings in open field suggested that notoginsenoides can modulate emotional responses in rats.

Chronic myeloid leukemia with thrombocythemic onset may be associated with different BCR/ABL variant transcripts.

Ph-positive chronic myeloid leukemia (CML) mimicking essential thrombocythemia (ET) at onset seems to be a distinct clinical entity. Whether this rare clinical form of CML is associated with single, specific variants of BCR/ABL transcripts is a matter of debate. Among 82 consecutive patients with Ph-positive CML, we identified 3 patients in which the disease mimicked ET at presentation, because of marked thrombocytosis and moderate leukocytosis, with few immature myeloid cells in peripheral blood and blood basophilia in 2 of them. Molecular analysis with the reverse transcriptase-polymerase chain reaction technique showed the presence of b2a2, b3a2, and b3a2-b2a2 transcript variants in the three patients, respectively. The results of our study together with a review of literature data suggest that different BCR/ABL transcript variants may occur in CML mimicking ET, without an apparently significant prevalence of one type.

Sensitive detection of circulating breast cancer cells by reverse-transcriptase polymerase chain reaction of maspin gene.

BACKGROUND: Maspin, a recently identified protein related to the family of serpins, is believed to play a role in human breast cancer. In an effort to improve the present methods of detection, we have developed a reverse-transcriptase polymerase chain reaction (RT-PCR) assay for maspin transcript to identify small numbers of mammary carcinoma cells in the peripheral blood and bone marrow of patients with breast cancer. PATIENTS AND METHODS: Five non-neoplastic mammary tissue samples, 13 breast cancer specimens as well as 17 peripheral blood and 4 bone marrow samples from normal subjects were screened for the presence of maspin mRNA by RT-PCR. The same assay was applied to peripheral blood or bone marrow samples obtained from 29 patients with stages I to IV breast cancer. RESULTS: By RT-PCR it was possible to amplify maspin mRNA in all of the primary and metastatic breast cancer specimens, but in none of the normal hemopoietic samples from healthy donors. Thus, detection of maspin transcript in the peripheral blood or marrow of a patient known to have breast cancer is indicative of the presence of mammary carcinoma cells. In reconstitution experiments, maspin RT-PCR reliably detected 10 mammary carcinoma cells in 1 million normal peripheral-blood mononuclear cells (PBMCs). None of the 9 patients with stages I, II, or III breast cancer had maspin transcript in peripheral blood. Of note, 3 of 9 patients with stage IV breast cancer receiving systemic therapy at the time of sample collection, but only 1 of 11 patients with stage IV not receiving therapy, had detectable maspin transcript in peripheral blood. Moreover, 3 marrow specimens from stage IV patients tested positive by this assay. CONCLUSIONS: This pilot study suggests that maspin RT-PCR assay is a sensitive, specific and sufficiently rapid method for detection of small numbers of circulating cells and marrow micrometastases in breast cancer patients. The possibility of applying this assay in the detection of tumor cell contamination of both marrow and stem-cell apheresis harvests of breast cancer patients merits further investigation.

Doxifluridine as palliative treatment in advanced gastric and pancreatic cancer patients.

BACKGROUND: The association of 5-fluorouracil (5-FU) and leucovorin is currently the most used combination in the treatment of advanced gastrointestinal neoplasms. Doxifluridine (d-FUR) is a fluoropyrimidine derivative that is converted into 5-FU inside tumor cells, where it is selectively cytotoxic. The oral administration of dFUR has been extensively investigated in colorectal carcinoma, and has been proven to be active and well tolerated. The purpose of this study was to test the effectiveness of the oral combination with dFUR plus l-leucovorin in gastric and pancreatic cancer patients. METHODS: A total of 50 cases were treated with l-leucovorin 25 mg, followed 2 h later by d-FUR 1,200 mg/m2 for 5 days; the cycles were repeated every 10 days. The regimen was given for a maximum of 36 cycles or until disease progression. Twenty-six patients had gastric cancer (all of whom were pretreated with polychemotherapy) and 24 had advanced pancreatic carcinoma. RESULTS: Objective responses were obtained in 4 (15%; 95% Cl 1-29) patients with gastric cancer, and in 1 (4%) with pancreatic cancer. The median response duration was 4 months. All of the responses were seen in patients previously treated with 5-FU-containing regimens. The median survival in gastric cancer patients was 7 months. Toxicity was moderate: WHO grade III and IV diarrhea was observed in 14% of the cases. CONCLUSIONS: This study indicates the efficacy of oral d-FUR plus l-leucovorin as palliative treatment in gastric cancer patients. The results in pancreatic carcinoma are disappointing but are in line with the published data relating to fluoropyrimidines.