Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. METHODS: Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25-50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. RESULTS: Between 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5-75%) for DPYD heterozygous carriers and 93.2% (42.9-100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924). CONCLUSIONS: Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.

Risk of thyroid disorders in adult and childhood Hodgkin lymphoma survivors 40 years after treatment.

Thyroid abnormalities are well reported following childhood treatment for Hodgkin Lymphoma (HL). Limited information exists for adult patients and after modern treatments. We analyzed risks of thyroid disorders in 237 female participants treated at the Royal Marsden Hospital 1970-2015. Multivariable analyses of risk according to treatment and time-related factors, survival analyses, and Cox regression modeling were undertaken. Overall, 33.8% of patients reported thyroid disorders (hypothyroidism 30.0% and thyroid nodules 6.8%). Cumulative prevalence was 42.9% by 40 years follow-up. Risks were greatest after supradiaphragmatic radiotherapy (RR = 5.0, p < 0.001), and increasing dose (RR = 1.03/Gy, p < 0.001). There was no association with a chemotherapy agent. Risks of thyroid disease were as raised following adult as childhood treatment. There was no trend in risk by decade of supradiaphragmatic radiotherapy treatment. Risks of thyroid disease after supradiaphragmatic radiotherapy are as great after adult as childhood treatment and persist after more recent treatment periods.

Telemedicine During the COVID-19 Pandemic: Impact on Care for Rare Cancers.

PURPOSE: Many patients with cancer, often those with rare cancers such as sarcomas, travel long distances to access expert care. The COVID-19 pandemic necessitated widespread changes in delivery of cancer care, including rapid adoption of telemedicine-based care. We aimed to evaluate the impact of telemedicine on patients, clinicians, and care delivery at the Royal Marsden Hospital (RMH) Sarcoma Unit during the pandemic. METHODS: Data were extracted from patient records for all planned outpatient appointments at the RMH Sarcoma Unit from March 23 to April 24, 2020. Patients and clinicians completed separate questionnaires to understand their experiences. RESULTS: Of 379 planned face-to-face appointments, 283 (75%) were converted to telemedicine. Face-to-face appointments remained for patients who needed urgent start of therapy or performance status assessment. Patients lived on average > 1.5 hours from RMH. Patient satisfaction (n = 108) with telemedicine was high (mean, 9/10), and only 48% (n = 52/108) would not want to hear bad news using telemedicine. Clinicians found telemedicine efficient, with no associated increased workload, compared with face-to-face appointments. Clinicians indicated lack of physical examination did not often affect care provision when using telemedicine. Most clinicians (n = 17; 94%) believed telemedicine use was practice changing; congruently, 80% (n = 86/108) of patients desired some telemedicine as part of their future care, citing reduced cost and travel time. CONCLUSION: Telemedicine can revolutionize delivery of cancer care, particularly for patients with rare cancers who often live far away from expert centers. Our study demonstrates important patient and clinician benefits; assessment of longer-term impact on patient outcomes and health care systems is needed.

Accountability in the NHS: the impact on cancer care.

Accountability of service delivery is becoming increasingly complex and never has this been more apparent than in the field of Oncology. Cancer care has an unrivalled level of complexity not only in the heterogeneity of management of the disease itself but increasingly in the myriad of service providers, specialities, policymakers and regulatory bodies overseeing its delivery. The stepwise series of changes to NHS structures over recent decades has had an enormous impact on our ability to answer key questions which lie at the heart of accountability: who is making the key decisions about changes to cancer care delivery? What are these reforms achieving? How can they be influenced? It is only through clear and transparent decision-making that we may have any hope of implementing, monitoring and influencing the effects of evidence-based change. However, with growing complexity of service structures and an increasing number of bodies developing ambitious and complex strategies, in a context of resource restraint and system pressures, it has become very difficult to answer these questions clearly. This increasing lack of clarity and transparency around such fundamental questions may mean that, despite there being such a pressing need and apparent desire for accountability in cancer care, paradoxically we may actually be deviating further and further away from this. Perhaps it is time for less complexity and for the decision-makers to get back to some fundamental principles which clinicians have embraced in evidence-based medicine: what is being done and by whom? Is this change beneficial and if not how can we influence change?

Continuing EGFR inhibition beyond progression in advanced non-small cell lung cancer.

The majority of patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) respond to first-line EGFR tyrosine kinase inhibitors (TKIs), but nearly all inevitably acquire resistance and develop disease progression. Conventional practice would be to switch treatments to second-line therapy. However, continuing TKIs beyond progression is becoming increasingly commonplace in patients with indolent, small volume asymptomatic growth, who may potentially continue to derive ongoing clinical benefit and to avoid a 'withdrawal tumour flare'. Nevertheless, there are limitations to our current criteria for assessing disease response, which are based on radiological assessments without considering symptomatic benefit, or the complex molecular and clinical heterogeneity of tumour growth and drug response patterns. In this article, we review the rationale for continuing EGFR inhibitors in patients with EGFR mutant NSCLC beyond disease progression and discuss strategies that have been pursued in the context of molecularly and clinically heterogeneous populations of tumour growth depending on the different clinical scenarios encountered. We discuss the management of systemic disease progression, including continuing EGFR TKIs alone, introducing a drug holiday, or combining TKIs with chemotherapy or other molecularly targeted agents. We also focus on approaches in managing patients with indolent, small volume asymptomatic growth (non-CNS oligometastatic disease progression) and those with oligometastatic EGFR mutant NSCLC with involvement of the central nervous system. We envision future precision medicine strategies through the use of next generation sequencing strategies of serial tumour rebiopsies and circulating plasma DNA to individualise the management for such patients during disease progression.

The use of moxifloxacin for acute exacerbations of chronic obstructive pulmonary disease and chronic bronchitis.

Chronic obstructive pulmonary disease is a common condition which causes considerable morbidity and mortality. It is a heterogenous disorder in which the majority of patients have chronic bronchitis. Bacterial infections are a major cause of acute exacerbations of both conditions which have a major impact on healthcare resources, quality of life and disease progression. Antibiotics are used to treat exacerbations involving purulent sputum production, together with increased breathlessness and/or sputum volume. Moxifloxacin is a quinolone antibiotic and is one of the treatment options. This article discusses pathophysiology of these diseases, moxifloxacin clinical studies and appropriate use of moxifloxacin.