The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

/pdf/mismatch-repair-deficiency-predicts-response-of-solid-tumors-2mgnsq9rdf.pdf

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

https://escholarship.org/content/qt7gf847t7/qt7gf847t7.pdf?t=qaejdd

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Summary Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015–35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015–35 is US$26·6 billion in low-income countries, $62·6 billion in lower-middle-income countries, and $94·8 billion in upper-middle-income countries, which amounts to $184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: $14·1 billion in low-income, $33·3 billion in lower-middle-income, and $49·4 billion in upper-middle-income countries—a total of $96·8 billion. Scale-up of radiotherapy capacity in 2015–35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278·1 billion in 2015–35 ($265·2 million in low-income countries, $38·5 billion in lower-middle-income countries, and $239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365·4 billion ($12·8 billion in low-income countries, $67·7 billion in lower-middle-income countries, and $284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16·9 billion in 2015–35 (–$14·9 billion in low-income countries; –$18·7 billion in lower-middle-income countries, and $50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104·2 billion (–$2·4 billion in low-income countries, $10·7 billion in lower-middle-income countries, and $95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(15)00222-3.pdf

Expanding global access to radiotherapy

http://static.guim.co.uk/ni/1432986420413/Ann-Oncol-2015.pdf

A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)

Global colorectal cancer burden in 2020 and projections to 2040

European laws on assisted suicide move in opposite directions.

End-of-life discussions are being left too late

Variations in breast cancer treatment and outcomes.

Two new studies have investigated trends in euthanasia and assisted suicide in Belgium and the Netherlands. Marianne Snijdewind and colleagues’ study focused on practices at a Dutch clinic for people whose previous requests for euthanasia or assisted suicide have satisfi ed the legal requirements but have nonetheless been rejected. During the first year, the clinic answered 645 requests for euthanasia or assisted suicide, of which 162 (25·1%) were granted. Overall Dutch physicians agreed to 32–45% of such requests—the smaller proportion at the clinic is to be expected given that these patients had been previously declined. Patients with cancer represent 79% of all euthanasia and assisted suicide deaths in the Netherlands. They only formed 22·8% of the granted requests at the clinic, probably because physicians are more willing to agree to cancer patients’ requests, so fewer attend the clinic in the first place. Patients who were married or living with their partner and those who had more than one child also had a greater chance of seeing their request granted. The investigators wrote that this suggested “that the views of family and domestic partners are important and that their involvement and support infl uence the clinic’s decisions”. In a research letter, Sigrid Dierickx and colleagues compared Belgian requests for euthanasia in 2013 with those of 2007. “The prevalence of euthanasia increased in all patient groups and in all health care settings”, noted the investigators. 10·4% of patients with cancer in the country died through euthanasia in 2013. In 2007, the proportion was 5·6%. The likelihood of a patient with cancer having a request for euthanasia granted increased from 64·4% to 77·5% over the same period. The investigators attributed the results to physicians becoming increasingly comfortable with the practice of euthanasia, a wider acceptance of its place in palliative care, and shifting attitudes in the population at large. “Eventually all civilised countries will legalise euthanasia and assisted suicide—it is really just a matter of time”, commented Julian Savulescu (Oxford University, Oxford, UK). He points out that fears of people being pressurised into suicide have not been borne out by the Dutch or Belgian experience. “People want to have control over their death, and there is no reason for the state to intervene in the liberty of one individual to access assisted suicide or euthanasia when another individual is prepared to provide it”, he said.

/pdf/trends-in-euthanasia-and-assisted-suicide-36b0ob8hlb.pdf

Talha Khan Burki

Papers

European laws on assisted suicide move in opposite directions.

End-of-life discussions are being left too late

Variations in breast cancer treatment and outcomes.

Trends in euthanasia and assisted suicide.

Lisa's Story: The Other Shoe