Immune Checkpoint Inhibitors and Opioids in Patients with Solid Tumours: Is Their Association Safe? A Systematic Literature Review.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent one of the most effective treatments for patients with cancer. As their activity relies on host immune system reactivity, the role of concomitant medications such as corticosteroids and antibiotics has been extensively evaluated. Preclinical data suggest that opioids may influence the immune system. METHODS: a systematic literature revision was performed using specific keywords on the major search engines. Two authors analysed all the studies and provided a selection of the following inclusion and exclusion criteria, respectively: 1. data collection of patients older than 18 years old affected by solid tumours; 2. description of ICIs efficacy in terms of PFS, OS, TTF, and ORR; 3. concomitant ICIs-opioids treatment and 1. language different from English; 2. not pertinent analyses. RESULTS: 523 studies were analysed, and 13 were selected and included in our series. A possible negative interaction between oral opioids and ICIs efficacy was observed. Most evidence was retrospective, and studies were heterogeneous. CONCLUSIONS: Even if oral opioids seem to impact negatively on ICIs efficacy in cancer patients, to date there is not sufficient evidence to avoid their prescription in this population.

The Path of Cicely Saunders: The "Peculiar Beauty" of Palliative Care.

This paper is aimed at focusing on the writings and the experience of the Hospice movement Founder, Dame Cicely Saunders. The in-depth analysis carried out had the objective of verifying if "the way" of Cicely to understand, live and propose palliative care was still current and "beautiful", so that we can nowadays refer to her fascinating "Original Palliative Care". With "beauty" we mean, on the one hand, a way able to allow a personal path of research of the meaning of the disease and of the care, both for those who care and for those who are cared for. On the other hand, it seems to us that Cicely strongly suggests how this path can not be carried out alone, but is only possible within the context of a network of relationships and support, in a so called "relational autonomy", for the patient, included in a "care ethics". The authors believe that the work extensively documents as the overall approach of Cicely, traditional but always to be rediscovered, is still today the most convincing way of conception and action of palliative care.

Systematic vs. on-demand early palliative care in gastric cancer patients: a randomized clinical trial assessing patient and healthcare service outcomes.

PURPOSE: Early palliative care (EPC) has shown a positive impact on quality of life (QoL), quality of care, and healthcare costs. We evaluated such effects in patients with advanced gastric cancer. METHODS: In this prospective, multicenter study, 186 advanced gastric cancer patients were randomized 1:1 to receive standard cancer care (SCC) plus on-demand EPC (standard arm) or SCC plus systematic EPC (interventional arm). Primary outcome was a change in QoL between randomization (T0) and T1 (12 weeks after T0) in the Trial Outcome Index (TOI) scores evaluated through the Functional Assessment of Cancer Therapy-Gastric questionnaire. Secondary outcomes were patient mood, overall survival, and family satisfaction with healthcare and care aggressiveness. RESULTS: The mean change in TOI scores from T0 to T1 was - 1.30 (standard deviation (SD) 20.01) for standard arm patients and 1.65 (SD 22.38) for the interventional group, with a difference of 2.95 (95% CI - 4.43 to 10.32) (p = 0.430). The change in mean Gastric Cancer Subscale values for the standard arm was 0.91 (SD 14.14) and 3.19 (SD 15.25) for the interventional group, with a difference of 2.29 (95% CI - 2.80 to 7.38) (p = 0.375). Forty-three percent of patients in the standard arm received EPC. CONCLUSIONS: Our results indicated a slight, albeit not significant, benefit from EPC. Findings on EPC studies may be underestimated in the event of suboptimally managed issues: type of intervention, shared decision-making process between oncologists and PC physicians, risk of standard arm contamination, study duration, timeliness of assessment of primary outcomes, timeliness of cohort inception, and recruitment of patients with a significant symptom burden. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01996540).

Palliative Sedation for the Terminally Ill Patient.

Palliative sedation (PS) is performed in the terminally ill patient to manage one or more refractory symptoms. Proportional PS, which means that drugs can be titrated to the minimum effective dose, is the form most widely used. From a quarter to a third of all terminally ill patients undergo PS, with a quarter of these requiring continuous deep sedation. The prevalence of PS varies according to the care setting and case mix. The most frequent refractory physical symptoms are delirium and dyspnea, but PS is also considered for existential suffering or psychological distress, which is an extremely difficult and delicate issue to deal with. Active consensus from the patient and advanced care planning is recommended for PS. The decision-making process concerning the continuation or withdrawal of other treatments is not the same as that used for PS. The practice differs totally from euthanasia in its intentions, procedures, and results. The most widely used drugs are midazolam and haloperidol for refractory delirium, but chlorpromazine and other neuroleptics are also effective. In conclusion, some patients experience refractory symptoms during the last hours or days of life and PS is a medical intervention aimed at managing this unbearable suffering. It does not have a detrimental effect on survival.

Systematic versus on-demand early palliative care: A randomised clinical trial assessing quality of care and treatment aggressiveness near the end of life.

AIM: Early palliative care (EPC) in oncology has shown sparse evidence of a positive impact on patient outcomes, quality of care outcomes and costs. PATIENTS AND METHODS: Data for this secondary analysis were taken from a trial of 207 outpatients with metastatic pancreatic cancer randomly assigned to receive standard cancer care plus on-demand EPC (standard arm) or standard cancer care plus systematic EPC (interventional arm). After 20 months' follow-up, 149 (80%) had died. Outcome measures were frequency, type and timing of chemotherapy administration, use of resources, place of death and overall survival. RESULTS: Some indices of end-of-life (EoL) aggressiveness had a favourable impact from systematic EPC. Interventional arm patients showed higher use of hospice services: a significantly longer median and mean period of hospice care (P = 0.025 for both indexes) and a significantly higher median and mean number of hospice admissions (both P < 0.010). In the experimental arm, chemotherapy was performed in the last 30 days of life in a significantly inferior rate with respect to control arm: 18.7% versus 27.8% (adjusted P = 0.036). Other non-significant differences were seen in favour of experimental arm. CONCLUSIONS: Systematic EPC showed a significant impact on some indicators of EoL treatment aggressiveness. These data, reinforced by multiple non-significant differences in most of the other items, suggest that quality of care is improved by this approach. This study is registered on ClinicalTrials.gov (NCT01996540).

Vinorelbine and fluorouracil plus leucovorin combination (ViFL) in patients with anthracycline and taxane-pretreated metastatic breast cancer: a phase II study.

PURPOSE: This phase II study was designed in order to evaluate efficacy and safety of the combination of vinorelbine (VNB), fluorouracil (FU) and leucovorin (LV) in patients with metastatic breast carcinoma (MBC) previously treated with anthracyclines and taxanes. METHODS: From 12/2003 to 12/2007, 51 women (median age 59) were treated. Performance status (PS) (ECOG) was 0-2 (median 0). The chemotherapy consisted of VNB 25 mg/sqm on day 1 added to FU and LV (following De Gramont schedule) on day 1 and 2. Treatment was repeated every 14 days. 518 cycles of CT were administered (median 12). Most common sites of metastatic spread were: bone, liver, lymph nodes, lung. RESULTS: We recorded three cases of G4 neuthropenia and in one case it was febrile; no others G4 toxicities were seen. G3 toxicities were more common, especially neuthropenia (8 patients) asthenia (4) mucositis (2) and Hand-Foot Syndrome (2). Overall response rate was 27.5% (14 patients had a PR) and disease control rate was 76.5%; 12 patients experienced disease progression. Median time to progression (TTP) was 7.70 months and overall survival (OS) was 18.70 months. CONCLUSIONS: Results demonstrate that the ViFL regimen has substantial activity in patients with MBC already treated with anthracyclines and taxanes. The combination may be considered a valid choice for the treatment of MBC. Better survival results were seen in patients with visceral metastases than bone involvement. The low response rate shows that the ViFL regimen is not suitable for the neoadjuvant setting.

Weekly irinotecan plus protracted venous fluorouracil infusion (WI-FI) in advanced colorectal cancer: a phase II study.

BACKGROUND: Irinotecan (IRI) is a topoisomerase I inhibitor active as first- or second-line chemotherapy in advanced colorectal cancer (ACRC). Its combination with fluorouracil (FU) increases the response rate and prolongs survival. In order to identify a new effective and less toxic schedule of administration, we planned this phase II study with weekly IRI and protracted venous infusion of FU (WI-FI regimen). The primary endpoint was the objective response rate. Secondary aims were to detect toxicity, progression-free survival (PFS) and overall survival (OS) of patients (pts). MATERIALS AND METHODS: On May 2000, a monoinstitutional study commenced with the following schedule of administration: IRI 80 mg/m2 on days 1, 8, 15, 22, 29 plus a 28-day protracted venous infusion of FU 200 mg/m2/day. The treatment was repeated every 35 days. Cycles were administered until a maximum of 6 courses, disease progression or unacceptable toxicity. RESULTS: By March 2005, 52 patients (30 males and 22 females) had entered the study. Their median age was 61.5 years and the median ECOG PS was 1. In total, 223 courses were administered (median 5 cycles/patient). Toxicity was low: neutropenia G3 and asthenia G3 were the most observed toxicities (5 pts each). No other grade 3-4 toxic side-effects were seen. Weekly IRI was interrupted in 11 pts, mostly related to problems with the central venous catheter. Following RECIST criteria, we observed 5 complete responses, 15 partial responses, 17 pts had stable disease, while in 15 disease progressed. The overall response rate was 38.5% and the disease control rate was 71.2%. Thirteen pts underwent surgical resection of their relapsing disease. The median PFS was 8.2 months and the median OS was 16.3 months. CONCLUSION: The WI-FI regimen is an active treatment with a good safety profile in patients with CRC. The low incidence of grade 3-4 toxicities justifies further evaluation of this combination.

Oxycodone controlled-release as first-choice therapy for moderate-to-severe cancer pain in Italian patients: results of an open-label, multicentre, observational study.

BACKGROUND AND OBJECTIVES: Cancer pain affects patients at all stages of the disease and there are clear guidelines for its management. Morphine is considered the first-choice strong opioid in the treatment of moderate-to-severe pain; however, numerous studies have shown that oxycodone controlled-release (CR) has a similar efficacy and safety profile. The purpose of this study was to evaluate the efficacy and tolerability of oxycodone CR as a first-line strong opioid for the treatment of moderate-to-severe pain in Italian cancer patients. METHODS: This was a prospective, open-label, multicentre, observational trial carried out at 15 locations across Italy. Patients with a referral for cancer-related pain of > or =5 on a 10-point numerical rating scale were enrolled. Patients were treated with oral oxycodone CR and monitored for 21 days. Dosage was individualized for each patient and up-titrated until effective pain control was achieved. Pain, adverse events and quality-of-life scores were assessed throughout the study. RESULTS: 390 patients (174 females and 216 males) with a mean age of 66 +/- 11 years were evaluated. The average daily dose ranged from 22.84 on day 1 to 40 mg/day on day 21. Pain intensity (assessed on a 10-point numerical rating scale) decreased significantly within 1 day of treatment commencement (p = 0.00001) and continued to decrease throughout the study period (from a mean 7.22 at baseline to a mean 2.11 points on day 21). Adverse events were mild to moderate in intensity and consisted of common opioid-related events. Ten patients (2.6%) discontinued the study because of adverse events and four (1%) because of uncontrolled pain. All aspects of activities of daily life assessed were improved by study end. CONCLUSIONS: Oxycodone CR is efficacious and well tolerated as a first-line strong opioid for the treatment of moderate-to-severe cancer-related pain in Italian patients.