Early switch from intravenous to oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis: the EASI-SWITCH RCT.

Background: Neutropenic sepsis is a common complication of systemic anticancer treatment. There is variation in practice in timing of switch to oral antibiotics after commencement of empirical intravenous antibiotic therapy. Objectives: To establish the clinical and cost effectiveness of early switch to oral antibiotics in patients with neutropenic sepsis at low risk of infective complications. Design: A randomised, multicentre, open-label, allocation concealed, non-inferiority trial to establish the clinical and cost effectiveness of early oral switch in comparison to standard care. Setting: Nineteen UK oncology centres. Participants: Patients aged 16 years and over receiving systemic anticancer therapy with fever (≥ 38°C), or symptoms and signs of sepsis, and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with a Multinational Association for Supportive Care in Cancer score of ≥ 21 and receiving intravenous piperacillin/tazobactam or meropenem for < 24 hours were eligible. Patients with acute leukaemia or stem cell transplant were excluded. Intervention: Early switch to oral ciprofloxacin (750 mg twice daily) and co-amoxiclav (625 mg three times daily) within 12-24 hours of starting intravenous antibiotics to complete 5 days treatment in total. Control was standard care, that is, continuation of intravenous antibiotics for at least 48 hours with ongoing treatment at physician discretion. Main outcome measures: Treatment failure, a composite measure assessed at day 14 based on the following criteria: fever persistence or recurrence within 72 hours of starting intravenous antibiotics; escalation from protocolised antibiotics; critical care support or death. Results: The study was closed early due to under-recruitment with 129 patients recruited; hence, a definitive conclusion regarding non-inferiority cannot be made. Sixty-five patients were randomised to the early switch arm and 64 to the standard care arm with subsequent intention-to-treat and per-protocol analyses including 125 (intervention n = 61 and control n = 64) and 113 (intervention n = 53 and control n = 60) patients, respectively. In the intention-to-treat population the treatment failure rates were 14.1% in the control group and 24.6% in the intervention group, difference = 10.5% (95% confidence interval 0.11 to 0.22). In the per-protocol population the treatment failure rates were 13.3% and 17.7% in control and intervention groups, respectively; difference = 3.7% (95% confidence interval 0.04 to 0.148). Treatment failure predominantly consisted of persistence or recurrence of fever and/or physician-directed escalation from protocolised antibiotics with no critical care admissions or deaths. The median length of stay was shorter in the intervention group and adverse events reported were similar in both groups. Patients, particularly those with care-giving responsibilities, expressed a preference for early switch. However, differences in health-related quality of life and health resource use were small and not statistically significant. Conclusions: Non-inferiority for early oral switch could not be proven due to trial under-recruitment. The findings suggest this may be an acceptable treatment strategy for some patients who can adhere to such a treatment regimen and would prefer a potentially reduced duration of hospitalisation while accepting increased risk of treatment failure resulting in re-admission. Further research should explore tools for patient stratification for low-risk de-escalation or ambulatory pathways including use of biomarkers and/or point-of-care rapid microbiological testing as an adjunct to clinical decision-making tools. This could include application to shorter-duration antimicrobial therapy in line with other antimicrobial stewardship studies. Trial registration: This trial is registered as ISRCTN84288963. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/140/05) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.

Neutropenic sepsis, or infection with a low white blood cell count, can occur following cancer treatment. Usually patients receive treatment with intravenous antibiotics (antibiotics delivered into a vein) for two or more days. Patients at low risk of complications from their infection may be able to have a shorter period of intravenous antibiotics benefitting both patients and the NHS. The trial compared whether changing from intravenous to oral antibiotics (antibiotics taken by mouth as tablets or liquid) 12­24 hours after starting antibiotic treatment ('early switch') is as effective as usual care. Patients could take part if they had started intravenous antibiotics for low-risk neutropenic sepsis. Patients were randomly allocated to 'early switch' or to usual care. The main outcome measured was treatment failure. Treatment failure happened if fever persisted or recurred despite antibiotics, if patients needed to change antibiotics, if they needed to be re-admitted to hospital or needed to be admitted to intensive care within 14 days or died. We had originally intended that 628 patients would take part, but after review of the design of the study the number needed to take part was revised to 230. We were not able to complete the trial as planned as unfortunately only 129 patients took part. As the trial was smaller than expected we were not able to draw conclusions as to whether 'early switch' is no less effective than usual care. Our findings suggest that 'early switch' might result in a shorter time in hospital initially; however, treatment failure was more likely to occur, meaning some patients had to return to hospital for further antibiotics. There were no differences in side effects and no serious complications from treatment or treatment failure (such as intensive care admission or death) among the 65 patients in the 'early switch' group. Patients were satisfied with 'early switch'. Early switch may be a treatment option for some patients with low-risk neutropenic sepsis who would prefer a shorter duration of hospital admission but accept a risk of needing hospital re-admission.

Early switch to oral antibiotic therapy in patients with low-risk neutropenic sepsis (EASI-SWITCH): a randomized non-inferiority trial.

OBJECTIVES: To determine whether early switch to oral antibiotic treatment in adults with neutropenic sepsis at low risk of complications is non-inferior to switching later. METHODS: This non-inferiority, parallel-group, randomized, open-label clinical trial enrolled UK adults hospitalized with neutropenic sepsis. Participants were randomly assigned to either switch to oral ciprofloxacin plus co-amoxiclav within 12-24 hours or to continue intravenous treatment for at least 48 hours. The primary outcome was a composite measure of treatment failure, 14 days after randomization. The non-inferiority margin was 15%. RESULTS: There were 129 participants from 16 centres and 125 were assessed for the primary outcome. Of these, 113 patients completed protocolized treatment and comprised the per-protocol population. In total, 9 (14.1%) of 64 patients in the standard care arm met the primary end point, compared with 15 (24.6%) of 61 in the early switch arm, giving a risk difference of 10.5% (1-sided 95% CI, -∞% to 22%; p 0.14). In the per-protocol population, 8 (13.3%) of the 60 patients in the standard care arm met the primary end point, compared with 9 (17%) of 53 in the intervention arm giving a risk difference of 3.7% (one-sided 95% CI, -∞% to 14.8%; p 0.59). Duration of hospital stay was shorter in the intervention arm (median 2 [inter-quartile range (IQR) 2-3] vs. 3 days [IQR 2-4]; p 0.002). DISCUSSION: Although non-inferiority of early oral switch was found in the per-protocol population, the intervention was not non-inferior in the intent-to-treat population.

Coriolus (Trametes) versicolor mushroom to reduce adverse effects from chemotherapy or radiotherapy in people with colorectal cancer.

BACKGROUND: Radiotherapy and chemotherapy are used to improve survival in colorectal cancer but adverse effects can be a problem. Severe adverse effects may result in dose reduction or cessation of treatment, which have an impact on survival. Coriolus versicolor (Trametes versicolor or 'Turkey Tail') mushroom and its extracts have been used by cancer patients to help with adverse effects. OBJECTIVES: To assess the effects of adjunctive Coriolus versicolor (Trametes versicolor) and its extracts on adverse effects and on survival during colorectal cancer treatment (chemotherapy and radiotherapy) compared with no adjunctive treatment. SEARCH METHODS: We searched databases including CENTRAL, MEDLINE, Embase, AMED and CINAHL, Chinese and Japanese databases, and trials registers to 12th April 2022 without restriction of language or publication status. We screened reference lists and attempted to contact researchers in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) investigating the efficacy and safety of Coriolus versicolor and its extracts in adult participants with a confirmed diagnosis of colorectal cancer, in addition to conventional treatment. Interventions included any preparation of Coriolus versicolor (raw, decoction, capsule, tablet, tincture, extract, injection), any part of the fungus (cap, stem, mycelium or whole), in any dose or regimen. Outcomes included adverse events rates, survival, disease progression and recurrence, response rates and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected studies, extracted outcome data, and assessed risk of bias. We evaluated the overall certainty of evidence using the GRADE approach. MAIN RESULTS: We included seven parallel RCTs (1569 participants). Six studies (1516 participants) were conducted in Japan and one study (53 participants) in China. Studies included both male and female participants with colorectal cancer (five studies), colon cancer (one study) or rectal cancer (one study). Participants were diagnosed with cancer ranging from stage II to stage IV. Coriolus was used in the form of an extract in all seven studies and was generally used after curative resection, although in one study it was used preoperatively. Duration of treatment with the extract varied between four weeks and three years. Chemotherapeutic regimens in six studies consisted of an oral fluoropyrimidine which was preceded by weekly intravenous 5-Fluorouracil (5-FU) in one study, by mitomycin C in two studies, and which was combined with folinic acid (Leucovorin) in two studies and with radiotherapy preoperatively in one study. XELOX (oxaliplatin intravenous infusion and capecitabine) was used in the remaining study. We found very low-certainty evidence of little to no effect of adjunctive treatment with Coriolus (in the form of an extract, polysaccharide-Krestin, PSK) on withdrawal from treatment due to adverse events  (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.45 to 2.34; 703 participants; 3 studies;). We are uncertain whether adjunctive Coriolus versicolor and its extracts compared to usual care alone resulted in a difference in adverse events including neutropenia (RR 0.41, 95% CI 0.24 to 0.71; 133 participants; 3 studies; very low certainty), oral cavity disorders such as oral dryness and mucositis (RR 0.37, 95% CI 0.13 to 1.03; 1022 participants; 5 studies; very low certainty), nausea (RR 0.73, 95% CI 0.44 to 1.22; 969 participants; 4 studies; very low certainty), diarrhoea (RR 0.77, 95% CI 0.32 to 1.86; 1022 participants; 5 studies; very low certainty), and fatigue (RR 0.76; 95% CI 0.33 to 1.78; 133 participants; 3 studies; very low certainty). We found low-certainty evidence of a small effect of adjunctive Coriolus on improved survival at five years compared with no adjunctive care (RR 1.08, 95% CI 1.01 to 1.15; 1094 participants; 3 studies; number needed to benefit (NNTB) = 16 (95% Cl 9 to 70). The effect at earlier time points was unclear. AUTHORS' CONCLUSIONS: Due to the very low certainty of evidence, we were uncertain about the effect of adjunctive Coriolus (in the form of an extract PSK) on adverse events resulting from conventional chemotherapy for colorectal cancer. This includes effects on withdrawal of treatment due to adverse events and on specific adverse outcomes such as neutropenia and nausea. The uncertainty in the evidence also means that it was unclear whether any adverse events were due to the chemotherapy or to the extract itself. While there was low-certainty evidence of a small effect on overall survival at five years, the influence of reduced adverse effects on this could not be determined. In addition, chemotherapy regimens used in assessing this outcome do not reflect current preferred practice.

Evaluating holistic needs assessment in outpatient cancer care--a randomised controlled trial: the study protocol.

INTRODUCTION: People living with and beyond cancer are vulnerable to a number of physical, functional and psychological issues. Undertaking a holistic needs assessment (HNA) is one way to support a structured discussion of patients' needs within a clinical consultation. However, there is little evidence on how HNA impacts on the dynamics of the clinical consultation. This study aims to establish (1) how HNA affects the type of conversation that goes on during a clinical consultation and (2) how these putative changes impact on shared decision-making and self-efficacy. METHODS AND ANALYSIS: The study is hosted by 10 outpatient oncology clinics in the West of Scotland and South West England. Participants are patients with a diagnosis of head and neck, breast, urological, gynaecological and colorectal cancer who have received treatment for their cancer. Patients are randomised to an intervention or control group. The control group entails standard care--routine consultation between the patient and clinician. In the intervention group, the patient completes a holistic needs assessment prior to consultation. The completed assessment is then given to the clinician where it informs a discussion based on the patient's needs and concerns as identified by them. The primary outcome measure is patient participation, as determined by dialogue ratio (DR) and preponderance of initiative (PI) within the consultation. The secondary outcome measures are shared decision-making and self-efficacy. It is hypothesised that HNA will be associated with greater patient participation within the consultation, and that shared decision-making and feelings of self-efficacy will increase as a function of the intervention. ETHICS AND DISSEMINATION: This study has been given a favourable opinion by the West of Scotland Research Ethics Committee and NHS Research & Development. Study findings will be disseminated through peer-reviewed publications and conference attendance. TRAIL REGISTRATION NUMBER: Clinical Trials.gov NCT02274701.

Management options for established chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a variety of chemotherapeutic agents. Clinicians are cognizant of the negative impact of CIPN on cancer treatment outcomes and patients' psychosocial functioning and quality of life. In an attempt to alleviate this problem, clinicians and patients try various therapeutic interventions, despite limited evidence to support efficacy of these treatments. The rationale for such use is mostly based on the evidence for the treatment options in non-CIPN peripheral neuropathy syndromes, as this area is more robustly studied than is CIPN treatment. In this manuscript, we examine the existing evidence for both CIPN and non-CIPN treatments and develop a summary of the best available evidence with the aim of developing a practical approach to the treatment of CIPN, based on available literature and clinical practice experience.

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNomS study.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.

Pain in patients attending a specialist cancer service: prevalence and association with emotional distress.

CONTEXT: We know little about how many outpatients of a modern cancer center suffer from clinically significant unrelieved pain and the characteristics of these patients to guide better care. OBJECTIVES: To determine the prevalence of clinically significant pain (CSP) in the outpatients of a regional cancer center and the association with distress and other variables. METHODS: A secondary analysis of cross-sectional, self-reported and clinical data from 2768 patients reattending selected clinics of a regional National Health Service cancer center in the U.K. Pain was measured using the pain severity scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, emotional distress was measured by the Hospital Anxiety and Depression Scale, and demographic and clinical data were taken from medical records. RESULTS: Fifty-four percent (95% confidence interval [CI] 52-56) of patients reported pain at least "a little" in the previous week and 18% (95% CI 17-20) at least "quite a bit" (CSP). The strongest independent associations of CSP were active disease (odds ratio [OR] 1.95, 95% CI 1.5-2.5) and emotional distress (OR 4.8, 95% CI 4-6). CONCLUSION: CSP is surprisingly common in outpatients of specialist cancer services, and it is strongly and independently associated with emotional distress. Better symptom management should consider pain and distress together.

Sleep problems in cancer patients: prevalence and association with distress and pain.

BACKGROUND: Although it is increasingly recognized that cancer patients often have sleep problems, we lack data on their prevalence and associations in representative clinical populations. We aimed to determine (i) the prevalence of sleep problems amongst outpatients of a cancer centre and (ii) the association with medical variables, emotional distress and pain. METHODS: Secondary analysis of self-report and medical data on 2862 cancer centre outpatients. Sleep problems were identified using the sleep item from the Patient Health Questionnaire-9: 'Over the last two weeks, how often have you been bothered by trouble falling or staying asleep or sleeping too much?' scored on a four-point frequency scale. Emotional distress was measured using the Hospital Anxiety and Depression Scale and pain using the subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Core 30 questionnaire. Medical data were obtained from the cancer centre clinical database. RESULTS: Sleep problems (bothered more than half the days during the previous 2 weeks) were reported by 30.2% (865/2862, 95% CI = 28.5 to 31.9) of the patients. They were common in both patients with active cancer (34.5%) and in cancer survivors (28.0%). There was only a modest association with cancer site and treatment status, but there was a strong association with pain (odds ratio = 2.7, 95% CI = 2.2 to 3.4) and emotional distress (odds ratio = 4.5, 95% CI = 3.7 to 5.6). CONCLUSIONS: Sleep problems are common in cancer outpatients and are strongly associated with pain and emotional distress. A combined approach to the management of sleep, pain and emotional distress is indicated. Copyright © 2011 John Wiley & Sons, Ltd.

The interface between medical oncology and supportive and palliative cancer care.

Traditionally, medical oncology has focused on the active period of diagnosis, treatment and follow-up of cancer patients, and palliative medicine, the pre-terminal and end-of-life phases. Palliative medicine physicians have particular expertise in communication and symptom control, especially, for example, with pain management. Medical oncologists also have need of excellent communication skills and knowledge of supportive care issues, such as the management of emesis, bone marrow suppression, mucositis, neuropathy, and symptoms created by treatment. This article examines the interface between medical oncology and supportive and palliative care to emphasize how each can benefit from the others.

Better off dead: suicidal thoughts in cancer patients.

PURPOSE: Cancer is associated with an increased risk of suicide and attempted suicide. However, we do not know how many cancer patients have thoughts that they would be better off dead or thoughts of hurting themselves. This study aimed to determine the prevalence of such thoughts in cancer outpatients and which patients are most likely to have them. PATIENTS AND METHODS: A survey of consecutive patients who attended the outpatient clinics of a regional cancer center in Edinburgh, United Kingdom. Patients completed the Patient Health Questionnaire-9 (PHQ-9), which included Item 9 that asks patients if they have had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Those who reported having had such thoughts for at least several days in this period were labeled as positive responders. Patients also completed the Hospital Anxiety and Depression Scale (HADS) and a pain scale. The participating patients' cancer diagnoses and treatments were obtained from the cancer center clinical database. RESULTS: Data were available on 2,924 patients; 7.8% (229 of 2,924; 95% CI, 6.9% to 8.9%) were positive responders. Clinically significant emotional distress, substantial pain, and--to a lesser extent--older age, were associated with a positive response. There was strong evidence of interactions between these effects, and emotional distress played the most important role. CONCLUSION: A substantial number of cancer outpatients report thoughts that they would be better off dead or thoughts of hurting themselves. Management of emotional distress and pain should be a central aspect of cancer care.

Endometrioid epithelial ovarian cancer : 20 years of prospectively collected data from a single center.

BACKGROUND: Clinicopathological features and outcome of women with endometrioid and serous ovarian adenocarcinoma were compared. METHODS: Between 1984 and 2004, baseline and follow-up data were prospectively recorded on 1545 patients with ovarian cancer. Of these, 270 had pure endometrioid tumors; 659 had pure serous adenocarcinoma of the ovary. Response to platinum-based chemotherapy (PBC) overall survival, stage-for-stage median progression-free survival (PFS), and cause-specific median survival were compared. Independent predictors of survival were examined by using multivariate analyses. RESULTS: Median age of diagnosis for patients with endometrioid tumors was younger than those with serous adenocarcinoma of the ovary (60 years vs 62 years; P = .013). They presented more often with early disease (stage I and II; 50% vs 17%; P < .001), had less ascites, and had better performance status both overall and for stage II and III disease. More endometrioid tumors were optimally debulked overall (71% vs 45%; P < .001), but there was no difference according to stage. Objective and CA125 PBC response rates were not significantly different, but median PFS was better for patients with endometrioid tumors (24 months vs 13 months; P < .0001) as was overall median survival (48 months vs 22 months; P < .0001). This relation remained for stage II and III disease and for moderately and poorly differentiated tumors. Patients with concurrent endometrioid ovarian and endometrial malignancies had a survival advantage compared with those with ovarian malignancies alone. Independent predictors of survival after PBC were histological type, debulking status, and disease stage. CONCLUSIONS: Despite similar PBC response rates, endometrioid histology is associated with better survival compared with serous adenocarcinoma of the ovary, even with stage III or poorly differentiated tumors.