Duration of overall survival in patients with cancer has lengthened due to earlier detection and improved treatments. However, these improvements have created challenges in assessing the impact of newer treatments, particularly those used early in the treatment pathway. As overall survival remains most decision-makers' preferred primary endpoint, therapeutic innovations may take a long time to be introduced into clinical practice. Moreover, it is difficult to extrapolate findings to heterogeneous populations and address the concerns of patients wishing to evaluate everyday quality and extension of life. There is growing interest in the use of surrogate or interim endpoints to demonstrate robust treatment effects sooner than is possible with measurement of overall survival. It is hoped that they could speed up patients' access to new drugs, combinations, and sequences, and inform treatment decision-making. However, while surrogate endpoints have been used by regulators for drug approvals, this has occurred on a case-by-case basis. Evidence standards are yet to be clearly defined for acceptability in health technology appraisals or to shape clinical practice. This article considers the relevance of the use of surrogate endpoints in cancer in the UK context, and explores whether collection and analysis of real-world UK data and evidence might contribute to validation.

Myeloma is one of the hardest cancers to diagnose in primary care due to its rarity and non-specific symptoms. A rate-limiting step in diagnosing myeloma is the clinician considering myeloma and initiating appropriate investigations. We developed and internally validated a risk prediction model to identify those with a high risk of having undiagnosed myeloma based on results from routine blood tests taken for other reasons. A case-control study, based on 367 myeloma cases and 1488 age- and sex-matched controls, was used to develop a risk prediction model including results from 15 blood tests. The model had excellent discrimination (C-statistic 0.85 (95%CI 0.83, 0.89)) and good calibration (calibration slope 0.87 (95%CI 0.75, 0.90)). At a prevalence of 15 per 100,000 population and a probability threshold of 0.4, approximately 600 patients would need additional reflex testing to detect one case. We showed that it is possible to combine signals and abnormalities from several routine blood test parameters to identify individuals at high-risk of having undiagnosed myeloma who may benefit from additional reflex testing. Further work is needed to explore the full potential of such a strategy, including whether it is clinically useful and cost-effective and how to make it ethically acceptable.

Supplementary Figure from Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients

The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are especially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and interruptions in delivery of non-pandemic medical services are yet to be fully understood. Using a real-world dataset of 323 consecutive newly diagnosed MM patients in England, we investigated the impact of the COVID-19 pandemic on routes to myeloma diagnosis, disease stage at presentation and relevant clinical outcomes. We demonstrate increasing MM presentations via emergency services and increased rates of bony and extra-medullary disease. Differences were seen in choice of induction therapy and the proportion of eligible patients undertaking autologous stem cell transplantation. Whilst survival was statistically inferior for emergency presentations, significant survival differences have yet to be demonstrated for the entire cohort diagnosed during the pandemic, making extended follow-up critical in this group. This dataset highlights wide-ranging issues facing MM patients consequent of the COVID-19 pandemic, with full impacts for clinicians and policy-makers yet to be elucidated.

Collection of peripheral blood stem cells (PBSCs) for autologous stem cell transplant (ASCT) requires mobilization from the bone marrow. There is variation in mobilization choice; during the COVID-19 pandemic BSBMT&CT guidelines recommended using granulocyte-colony stimulating factor (G-CSF) alone to minimize the use of chemotherapy. We report on the impact of mobilization regimen on stem cell collection, and whether IMiD-containing induction therapy impacts on mobilization and consequently transplant engraftment times for 83 patients undergoing ASCT at Leeds Teaching Hospitals. Cyclophosphamide plus G-CSF (cyclo-G) mobilization yielded more CD34+ cells (8.94 vs. 4.88 ×106/kg, p = < 0.0001) over fewer days (1.6 vs. 2.4 days, p = 0.007), and required fewer doses of salvage Plerixafor than G-CSF only (13.6% vs. 35%, p = 0.0407). IMiD-containing induction impaired all of these factors. CD34+ doses > 8×106/kg were more frequent with Cyclo-G (62% vs. 11%, p = 0.0001), including for those receiving IMiD 1st line induction (50% vs. 13.3%, p = 0.0381). Note that 92.6% of those receiving IMiD-free inductions were mobilized with Cyclo-G. The novel agents used in modern induction regimens (e.g Daratumumab) have been shown to impair yields, increasing the importance of optimizing mobilization regimens in the first instance. Furthermore, as cellular therapies become established in the management of multiple myeloma emerging data highlights the potential benefits of stem cell top up in the management of the haematological toxicities of these therapies. Our findings support re-adoption of Cyclo-G as the gold standard for mobilization to optimize PBSC harvesting and ensure sufficient cells for subsequent ASCTs.

Age-related immune dysfunction is primarily mediated by immunosenescence which results in ineffective clearance of infective pathogens, poor vaccine responses and increased susceptibility to multi-morbidities. Immunosenescence-related immunometabolic abnormalities are associated with accelerated aging, an inflammatory immune response (inflammaging) and ultimately frailty syndromes. In addition, several conditions can accelerate the development of immunosenescence, including cancer. This is a bi-directional interaction since inflammaging may create a permissive environment for tumour development. Multiple myeloma (MM) is a mature B-cell malignancy that presents in the older population. MM exemplifies the interaction of age- (Host Response Biology; HRB) and disease-related immunological dysfunction, contributing to the development of a frailty syndrome which impairs the therapeutic impact of recent advances in treatment strategies. Understanding the mechanisms by which accelerated immunological aging is induced and the ways in which a tumour such as MM influences this process is key to overcoming therapeutic barriers. A link between cellular mitochondrial dysfunction and the acquisition of an abnormal immune phenotype has recently been described and has widespread physiological consequence beyond the impact on the immune system. Here we outline our current understanding of normal immune aging, describe the mechanism of immunometabolic dysfunction in accelerating this process, and propose the role these processes are playing in the pathogenesis of MM.

Abstract The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are es-pecially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and inter-ruptions in delivery of non-pandemic medical services are yet to be fully understood. Using a real-world dataset of 323 consecutive newly diagnosed MM patients in England, we in-vestigated the impact of the COVID-19 pandemic on routes to myeloma diagnosis, disease stage at presentation and relevant clinical outcomes. We demonstrate increasing MM presentations via emergency services and increased rates of bony and extra-medullary dis-ease. Differences were seen in choice of induction therapy and the proportion of eligible patients undertaking autologous stem cell transplantation. Whilst survival was statistically inferior for emergency presentations, significant survival differences have yet to be demon-strated for the entire cohort diagnosed during the pandemic, making extended follow-up critical in this group. This dataset highlights wide-ranging issues facing MM patients conse-quent of the COVID-19 pandemic, with full impacts for clinicians and policy-makers yet to be elucidated.

Background Netrin-1 is a laminin class protein that guides the axonal during the first embryonic development, has pushing and pulling properties, and has axonal chemoattractant activity. Netrin-1 has been shown to increase the effect of fibrosis in mouse lung and human SSc lung cell cultures. In this study, we aimed to investigate the relationship between Netrin-1 and Systemic sclerosis (SSc) and to emphasize the role of Netrin-1 in the pathophysiology of SSc by increasing the known VEGF and M2 macrophage expression, which supports the fibrotic process. Methods The study included 56 SSc patients with a mean age of 48·.08±13.59 years and 58 healthy volunteers with a mean age of 48.01±11.59 years. SSc organ involvements were scanned retrospectively from patient files, and patients were grouped according to SSc complications. Calculation of Netrin-1 levels was performed using a quantitative sandwich enzyme immunoassay method with an ELISA kit (Elabscience, Texas, USA; catalog number: E-EL-H2328; lot number: GZWTKZ5SWK). The modified Rodnan skin score (mRSS) was used for skin thickness scoring in SSc patients. Results The median value of Netrin-1 was found to be significantly higher in SSc (268.8 [82.75-1006.64]) than in controls (108.63 [21.02-351.49]) (p<0.0001). In ROC analysis, a cut-off value of 354.24 for Netrin in SSc was found to provide a sensitive confidence interval with 32.8% sensitivity and 98.3% specificity (AUC[95% CI]: 0.746-0.895, p<0.0001). There was no significant correlation between Netrin-1 level, organ involvement in SSc, and mRSS (p>0.05). Conclusion We found a significant relationship between Netrin-1 levels and SSc disease in this study. Our study is the first clinical study in which Netrin-1 elevation was demonstrated in SSc patients.

AbstractImproving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec–associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.

Background The treatment paradigm for multiple myeloma (MM) continues to evolve with the development of novel therapies and the earlier adoption of continuous treatments into the treatment pathway. Lenalidomide-refractory patients now represent a challenge with inferior progression free survival (PFS) reported to subsequent treatments. We therefore sought to describe the natural history of MM patients following lenalidomide in the real world. Methods This was a retrospective cohort review of patients with relapsed MM who received lenalidomide-based treatments in the U.K. Data were collected for demographics, subsequent therapies, treatment responses, survival outcomes and clinical trial enrollment. Results 198 patients received lenalidomide-based treatments at a median of 2 prior lines of therapy at a median of 41 months (range 0.5-210) from diagnosis. 114 patients (72% of 158 evaluable) became refractory to lenalidomide. The overall survival (OS) after lenalidomide failure was 14.7 months having received between 0-6 subsequent lines of therapy. Few deep responses were observed with subsequent treatments and the PFS to each further line was < 7 months. There was a steep reduction in numbers of patients able to receive further treatment, with an associated increase in number of deaths. The OS of patients progressing on lenalidomide who did not enter a clinical trial incorporating novel agents was very poor (8.8 months versus 30 months, p 0.0002), although the trials group were a biologically fitter group. Conclusion These data demonstrate the poor outcomes of patients failing lenalidomide-based treatments in the real world, the highlight need for more effective treatments.

SummaryPatients with haematological malignancies have a high risk of severe infection and death from SARS‐CoV‐2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS‐CoV‐2 infection and active haematological cancer. The primary end‐point was all‐cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1–2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96–1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09–5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08–2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti‐CD19/anti‐CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS‐CoV‐2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti‐CD19/anti‐CD20 treatments.

Waldenström macroglobulinemia (WM) is a rare malignancy in which clonal B cells infiltrate the bone marrow and give rise to a smaller compartment of neoplastic plasma cells that secrete monoclonal immunoglobulin M paraprotein. Recent studies into underlying mutations in WM have enabled a much greater insight into the pathogenesis of this lymphoma. However, there is considerably less characterization of the way in which WM B cells differentiate and how they respond to immune stimuli. In this study, we assess WM B-cell differentiation using an established in vitro model system. Using T-cell-dependent conditions, we obtained CD138+ plasma cells from WM samples with a frequency similar to experiments performed with B cells from normal donors. Unexpectedly, a proportion of the WM B cells failed to upregulate CD38, a surface marker that is normally associated with plasmablast transition and maintained as the cells proceed with differentiation. In normal B cells, concomitant Toll-like receptor 7 (TLR7) activation and B-cell receptor cross-linking drives proliferation, followed by differentiation at similar efficiency to CD40-mediated stimulation. In contrast, we found that, upon stimulation with TLR7 agonist R848, WM B cells failed to execute the appropriate changes in transcriptional regulators, identifying an uncoupling of TLR signaling from the plasma cell differentiation program. Provision of CD40L was sufficient to overcome this defect. Thus, the limited clonotypic WM plasma cell differentiation observed in vivo may result from a strict requirement for integrated activation.

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10−9) with opposing effects between CLL (P = 1.97 × 10−8) and HL (P = 3.31 × 10−3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10−12) was associated with increased CLL and HL risk (P = 4.68 × 10−12), and reduced MM risk (P = 1.12 × 10−2), and Gly70 in HLA-DQB1 (P = 3.15 × 10−10) showed opposing effects between CLL (P = 3.52 × 10−3) and HL (P = 3.41 × 10−9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

Multiple myeloma (MM) is characterized by an increased risk of infection due to the immunosuppressive effect of the disease and conjointly of therapy. Furthermore, there is impaired responses to vaccination to counter the infection risk. The factors that underpin defective B-cell homeostasis and effective humoral immunity are not clear, nor are the extent of the defects. Also, the level of impaired humoral immunity in MGUS is not fully understood. The aim of this study was to delineate the circulating B-cell populations and recall antibody responses in patients with MGUS & MM, compared to age-matched controls, correlating with the responsiveness to vaccinations, incidence of infective complications and concomitant therapy. We performed comprehensive B-cell immunophenotyping by multi-parameter flow cytometry of peripheral blood samples from patients with MGUS (n=16), asymptomatic MM (n=18) and MM (n=108) with a median age of 63 years (range 38-94) comparing them to age-matched controls (n=9). B-cell subsets included naive (CD19+CD27-), memory (CD19+CD27+; non-switch CD19+IgD+CD27+, switch CD19+IgD-CD27+), transitional (CD19+CD27-CD24hiCD38hi) & regulatory (CD19+CD27+CD24hi) B-cells. Serum uninvolved total IgG, IgM & IgA levels along with vaccine-specific antibody responses were analysed. There is a progressive decrease in the uninvolved immunoglobulin classes with significant reduction in total IgA (p=0.006) and IgM levels (p=0.007) in aMM/MM compared to MGUS & control (Figure 1). When anti-pneumococcal antibodies were measured, only 30% of aMM/MM patients had adequate protective levels compared to 79% of age-matched controls, with 40% of aMM/MM patients with inadequate levels experiencing recurrent respiratory tract infections compared to 25% of aMM/MM patients with adequate proactive antibodies. Patients with MGUS, aMM and MM have lower total B-cell numbers compared to controls (1-way ANOVA p=0.004; Figure 1). The reduction in B-cell numbers were primarily the consequence of reduced memory B-cells (percentage and absolute 1-way ANOVA p aMM>MM). Furthermore, a correlation with total IgG levels & memory B-cell numbers is evident (r2=-0.053) & progressive reduction in memory B-cell numbers is seen with advancing cycles of therapy. The ratio of switch:non-switch memory B-cells is unaltered (control 1.05, MGUS 0.53, aMM 1.41 & MM 1.49; 1-way ANOVA p=ns). Conversely, there is a compensatory increase in the percentage of transitional B-cells when increasing disease stage is compared to controls (control 7.38% (95%ci 4.9,9.9) vs MGUS 14.0% (95%ci 7.4, 20.7) vs aMM 14.95% (95%ci 8, 21.9); 1-way ANOVA p Disclosures No relevant conflicts of interest to declare.

We report a case of opioid withdrawal in a patient with metastatic lung cancer. This occurred approximately 56 hours after switching from oral modified-release oxycodone to alfentanil continuous subcutaneous infusion (CSCI). Symptoms were rapidly relieved after administration of small subcutaneous aliquots of oxycodone. Mrs. L. was a 50-year-old nonsmoker with squamous cell carcinoma of the lung first diagnosed in October 2009. At presentation, the tumor was staged as T3, N2, and M1, and she was initially treated with chemotherapy. This was poorly tolerated and discontinued after two cycles. Scans two months after diagnosis revealed rapidly progressive disease, with metastatic deposits in the spinal column, lungs, liver, and brain. A short course of cranial radiotherapy was given at this stage, which effectively eliminated progressive neurological symptoms. The patient was admitted to our hospice in January 2010 because of poor pain control. She gave a complex pain history that predominantly related to underlying spinal column disease, in addition to neuropathic arm pain secondary to apical invasion of the brachial plexus by her primary tumor. On admission, she received four fractions of radiotherapy to the thoracic spine because of incipient cord compression, with good effect. After radiotherapy, the primary symptom concerns were brachial plexus pain, swelling of the left arm, and thoracic spine pain. Initially, the pain responded well to increases in the oral oxycodone dose, but gradual general deterioration and malaise necessitated a switch to a CSCI of oxycodone. A conversion ratio of 50% was used initially, resulting in a 120 mg CSCI over 24 hours. The ongoing tumor invasion and associated escalation in analgesic requirements resulted in the dose increasing to a maximum of 160 mg. Pain control remained poor despite increased analgesia; in addition, renal function deteriorated to an estimated glomerular filtration rate of 15. This change, along with associated symptoms of opioid toxicity, necessitated a switch to a CSCI alfentanil infusion. Mrs. L. was started on a 12 mg CSCI of alfentanil over 24 hours, with 1 mg subcutaneous alfentanil boluses when required. This represented an overall dose reduction in her oxycodone dose, to account for the toxicity symptoms that she experienced (usual conversion ratio 7.5:1, equivalent to 16 mg alfentanil over 24 hours).1Urch C.E. Carr S. Minton O. A retrospective review of the use of alfentanil in a hospital palliative care setting.Palliat Med. 2004; 18: 516-519Crossref PubMed Scopus (9) Google Scholar The patient initially responded well to this, requiring significantly decreased “as required” analgesia and reporting feeling general improvement. Approximately 48 hours after the switch from oxycodone, the patient awoke in a distressed and agitated state. She exhibited symptoms of a classic opioid withdrawal syndrome. She was unable to maintain a comfortable position and was writhing in pain. Mrs. L. complained of cramping discomfort in her left arm and abdomen, nausea, and persistent uncontrolled tremor bilaterally. She was distressed and sweating profusely. The pain and distress were initially managed with additional doses of alfentanil 1 mg subcutaneous injection and midazolam 2.5 mg subcutaneous injection. She received a total of 4 mg alfentanil and 10 mg of midazolam over two hours, but with no improvement in her pain or agitation. Following this, an additional dose of 20 mg subcutaneous oxycodone was given; within 20 minutes, this resulted in complete relief of symptoms. One further subcutaneous oxycodone injection was required four hours later to maintain symptom control after a less severe exacerbation of the symptoms described above. Alfentanil is a synthetic derivative of fentanyl and a selective μ-receptor agonist.2Egan T.D. Minto C.F. Hermann D.J. et al.Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers.Anesthesiology. 1996; 84: 821-833Crossref PubMed Scopus (356) Google Scholar It possesses a number of characteristics that distinguish it from its parent compound. The important properties that differentiate alfentanil from fentanyl include a more rapid onset, shorter duration of action, and decreased volume of distribution.3Larijani G. Goldberg M. Alfentanil hydrochloride: a new short acting narcotic analgesic for surgical procedures.Clin Pharm. 1987; 6: 275-282PubMed Google Scholar The drug is less lipophilic than fentanyl but significantly more lipophilic than morphine.4Hill H.F. Coda B.A. Mackie A.M. Iverson K. Patient-controlled analgesia infusions: alfentanil versus morphine.Pain. 1992; 49: 301-310Abstract Full Text PDF PubMed Scopus (34) Google Scholar It is metabolized in the liver by cytochrome PYP3A4 to inactive compounds, does not accumulate in renal failure, and is available as injection only.3Larijani G. Goldberg M. Alfentanil hydrochloride: a new short acting narcotic analgesic for surgical procedures.Clin Pharm. 1987; 6: 275-282PubMed Google Scholar The primary role of alfentanil is in pain relief during anesthesia, as its short half-life simplifies the titration of analgesia. However, more recently the drug is finding favor among palliative care physicians treating patients with poor renal function and in those who suffer from accumulation of the toxic metabolites of opioids such as morphine.5Hall T. Hardy J. The lipophilic opioids: fentanyl, alfentanil, sufentanil and remifentanil.in: Davis M. Glare P. Hardy J. Opioids in cancer pain. Oxford University Press, Oxford2005Google Scholar Oxycodone is a strong opioid and shares many properties with morphine. It is metabolized in the liver via CYP3A to noroxycodone and via CYP2D6 to oxymorphone and noroxycodone, although it is the parent drug that is believed to provide the primary antinociceptive effect.6Heiskanen T. Olkkola K.T. Kalso E. Effects of blocking CYP2D6 on oxycodone.Clin Pharmacol Ther. 1998; 64: 603-611Crossref PubMed Scopus (212) Google Scholar The parenteral equivalence of morphine to oxycodone is now thought to be approximately 1:1.7Kalso E. Vainio A. Morphine and oxycodone in the management of cancer pain.Clin Pharmacol Ther. 1990; 47: 639-646Crossref PubMed Scopus (247) Google Scholar, 8Silvasti M. Rosenberg P. Seppälä T. Svartling N. Pitkänen M. Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia.Acta Anaesthesiol Scand. 1998; 42: 576-580Crossref PubMed Scopus (130) Google Scholar Oxycodone metabolism is affected by hepatic impairment and renal impairment, resulting in elimination half-life increases of up to two hours. Despite this, oxycodone is believed to cause less toxicity than morphine in patients with mild/moderate renal impairment because of its predominantly hepatic metabolism.6Heiskanen T. Olkkola K.T. Kalso E. Effects of blocking CYP2D6 on oxycodone.Clin Pharmacol Ther. 1998; 64: 603-611Crossref PubMed Scopus (212) Google Scholar An opioid withdrawal syndrome has been described previously in patients switching from an oral opioid to transdermal fentanyl patches.9Donner B. Zenz M. Tryba M. Strumpf M. Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain.Pain. 1996; 64: 527-534Abstract Full Text PDF PubMed Scopus (263) Google Scholar Donner et al. describe an incidence of approximately 10% in cancer pain patients when converting from oral morphine to transdermal fentanyl and good control of these symptoms with rescue doses of morphine. Although the evidence in a palliative care setting is limited and in the form of isolated case reports only,10McMunnigall F. Welsh J. Opioid withdrawal syndrome on switching from hydromorphone to alfentanil.Palliat Med. 2008; 22: 191-192Crossref PubMed Scopus (5) Google Scholar the increasing use of alfentanil and fentanyl makes recognition of these potential side effects increasingly important. This is the first presentation of an opioid withdrawal syndrome seen after opioid switching in our clinical practice, despite the treatment of several patients with a similar regimen previously. This may be accounted for by the high intra- and interindividual variability with alfentanil, both in terms of its pharmacodynamic properties and its opioid receptor affinity. Current theories on this withdrawal phenomenon center around the rapid subcutaneous redistribution of alfentanil, causing a temporary reduction in its bioavailability. This is hypothesized to result in a relative decrease in the patient’s circulating opioid concentration and subsequent development of withdrawal symptoms in the short term. The above case report appears to correspond with this description, and its case is strengthened by relief of symptoms with subcutaneous oxycodone. In conclusion, alfentanil is becoming increasingly popular in the palliative care environment. It is important to consider the high intraindividual variability in terms of potency and be mindful of possible opioid withdrawal syndromes encountered in certain patient populations. Early recognition of these problems will help to prevent unnecessary patient suffering in the future.