Multiparametric magnetic resonance and Prostate Cancer

‘Strong Argument’ For MP-MRI Triage In High PSA Level Men
Multiparametric magnetic resonance imaging could improve detection of clinically significant prostate cancer and avoid clinically insignificant diagnoses

Date: 23 Jan 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Prostate Cancer / Imaging, Diagnosis and Staging

medwireNews: PROMIS trial findings support the use of multiparametric magnetic resonance imaging (MP-MRI) for men with high levels of serum prostate-specific Antigen (PSA).

“Using MP-MRI as a triage test would reduce the problem of unnecessary biopsies in men who have a low risk of harbouring clinically significant cancer, reduce the diagnosis of clinically insignificant disease and improve the detection of clinically significant cancers”, say Hashim Ahmed, from University College London in the UK, and co-investigators.

The PROMIS study reports on findings for men with a PSA of up to 15 ng/mL who underwent MP-MRI followed by both transrectal ultrasound (TRUS)-guided biopsy (10–12 cores), and the reference test template prostate mapping (TPM)-biopsy (cores removed every 5 mm).

TPM-biopsy identified prostate cancer in 71% of 576 men, of whom 40% had clinically significant disease, defined as a Gleason score of 4+3 or higher, or a maximum cancer core length of at least 6 mm.

MP-MRI was significantly more sensitive at detecting clinically significant prostate cancer than TRUS-guided biopsy (93 vs 48%), albeit with significantly poorer specificity (41 vs 96%).

In addition, MP-MRI had a significantly better negative predictive value than TRUS-guided biopsy (89 vs 74%) and significantly lower positive predictive value (51 vs 90%).

“Using MP-MRI to triage men might allow 27% of patients [to] avoid a primary biopsy”, the researchers explain, as well as “diagnosis of 5% fewer clinically insignificant cancers”.

They continue: “If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all.”

Hashim Ahmed et al conclude: “Cost-effectiveness analyses of the PROMIS data are underway and will be reported elsewhere, but the primary outcome data provide a strong argument for recommending MP-MRI to all men with an elevated serum PSA before biopsy.”

Reference

Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet; Advance online publication 19 January 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(16)32401-1

Powerful Ideas for Global Access to Medicines. NEJM

Powerful Ideas for Global Access to Medicines
Suerie Moon, M.P.A., Ph.D.

January 18, 2017DOI: 10.1056/NEJMp1613861




One of the few issues uniting U.S. voters in the 2016 election was outrage over the high prices of medicines. From the quadrupling of EpiPen prices to $1,000-per-pill hepatitis C treatments, from six-digit pricing of cancer drugs to the 55-fold price increase on a 62-year-old toxoplasmosis drug, the scandals keep coming. In Europe, where government involvement in price negotiations means that new drugs, diagnostics, and vaccines (“medicines”) can cost less than half their U.S. prices, there is nevertheless serious concern that yearly price increases will break health system budgets. Worldwide drug spending grew by about 9% in 2014 and 2015, outpacing both overall health expenditures and economic growth.1

But what has recently been headline news in high-income countries has long been a concern everywhere else. Whether low- and middle-income countries (LMICs) are struggling to treat millions of people living with HIV or to immunize refugee children against pneumonia, unaffordable prices mean that many people simply go without. Meanwhile, despite billions of public and private dollars invested in pharmaceutical research and development, urgent needs for new antibiotics and tools for other public health priorities go unmet. Unaffordable medicines and inadequate innovation have become global issues. Like climate change, they require new public policies and international cooperation.

Responding to concerns raised by patients and health advocates worldwide, in 2015 United Nations (UN) Secretary General Ban Ki-Moon convened a High-Level Panel on Access to Medicines led by two former heads of state, Ruth Dreifuss of Switzerland and Festus Mogae of Botswana, together with 13 international experts with wide-ranging perspectives. Even before the report was published in September 2016 (www.unsgaccessmeds.org/final-report), it had attracted an unusual degree of attention — both positive and negative — from governments, the pharmaceutical industry, and civil society. Some of the reaction, epitomized by the U.S. Chamber of Commerce statement “condemn[ing the] U.N. report attacking patents,”2 reflected a decades-old debate over the appropriate relationship between intellectual property monopolies and medicine prices. Yet the report does not generally go beyond preexisting international agreements on patents. Rather, the true source of consternation may be that it reframes the access-to-medicines challenge not only as involving prices in LMICs, but also as requiring systemic changes to the prevailing research-and-development business model for the sake of all countries. The panel then advances some powerful ideas regarding such changes.

One of those ideas is transparency. Reliable, thorough public information is not generally available on the safety, efficacy, prices, patent status, sources of investment, and costs of developing lifesaving medicines. Given its profound implications for the public interest, the drug-development system is shrouded in a disproportionate degree of secrecy. The panel recommended that governments mandate disclosure of information on various aspects of pharmaceutical development, including research-and-development costs. Depending on the information source and the methods used, estimates of the cost of developing a new drug vary by a factor of 40 or more — ranging from $92 million to $4.2 billion.3 Transparency could introduce some measure of reason and evidence into heated pricing debates, which too often deteriorate into hyperbolic claims that any interference with free-market pricing would destroy innovation. A more granular understanding of research and development could also shed light on the efficiency of the processes involved and spark debate about how society ought to appropriately compensate investment, outcomes, and risk and calibrate financial rewards to the degree of therapeutic advance offered.

Transparency is also key to another powerful idea endorsed by the panel: ensuring public return on public investment in medicine development. Drug development is a public–private enterprise, with the public investing in basic research and early-stage discovery through taxpayer funding of academic and public laboratories and then purchasing the medicines that private firms develop through insurance policies or out-of-pocket expenditures. In areas in which the market fails to offer adequate incentives for innovation — such as neglected diseases, emerging infectious diseases, or antimicrobial resistance — public funding and priority setting play an even greater role, subsidizing all stages of product development. For example, the U.S. government’s Biomedical Advanced Research and Development Authority has funded private firms to develop medicines for use in potential outbreaks and has obtained approval from the Food and Drug Administration for 24 products since its founding in 2006. Transparency regarding public contributions to the research underlying a medicine could provide a foundation for tempering excessive pricing, either in advance through conditions imposed on public financing or after development through government regulation.

The report also calls for testing and implementing new business models of research and development that would build affordability into the product-development process by delinking research financing from end-product prices. Some such models have already been proven to work in not-for-profit drug-development efforts. For example, with $290 million from public funds and philanthropic contributions, the Drugs for Neglected Diseases Initiative (DNDi) put 26 candidate products into the development pipeline and brought 6 to market in 10 years; because the research costs have already been covered, DNDi’s products can be sold for approximately the cost of production.4 Though there are important differences between drug development for neglected diseases and other therapeutic areas, this example offers proof of principle regarding better ways to manage public and private investments to channel research and development in the public interest.

Finally, the panel called for governments and companies to adhere to established agreements to protect access to medicines under international trade rules. For example, governments have the authority to decide when a private patent right can be set aside in the interest of public health — a right that has been reaffirmed in every relevant UN political declaration since 2001. Though the pharmaceutical industry has criticized the report as an attack on patents, the panel in fact recommended only that preexisting agreements be enforced; it did not recommend additional patent flexibilities beyond what has been agreed on for 15 years. Indeed, some panel members and civil-society organizations expressed disappointment that it did not call for a more dramatic overhaul of intellectual-property treaties.

Among the report’s authors is the chief executive officer of GlaxoSmithKline (GSK), Andrew Witty, who has occasionally become a thorn in his industry’s side by taking positions ahead of the curve. For example, he has called the $1 billion research-and-development price tag a myth reflecting inefficiencies rather than required costs; he expanded GSK’s policy of licensing generic versions of patented medicines in some LMICs beyond HIV to include cancer; and he has endorsed new research-and-development models to combat antimicrobial resistance and pathogens of pandemic potential. His peers may wish to reexamine some of the business models advanced in the report, which could continue rewarding innovation while satisfying growing public demands for affordability and needs-driven innovation.

Given the charged politics of debates over access to medicines, I believe Secretary General Ban was courageous to convene this panel — though the report’s fate in the UN system is uncertain, given that there is a new secretary general, a new U.S. president, and a new director general of the World Health Organization in 2017. Nevertheless, the panel’s greatest impact may be realized not through intergovernmental talks, but by stimulating public debate over ways of reforming the research-and-development system to better serve the global public interest. The Netherlands’ trade and health ministers recently echoed three panel recommendations, calling for transparency of pharmaceutical research-and-development costs, adequate public return on public investment, and testing of new business models.5

This report comes at a time when the public appetite for change is growing, the pharmaceutical industry’s reputation is in the doldrums, and demand for a more equitable global trade system is building. It puts forth ideas that deserve a fair hearing in countries struggling to provide access to medicines for their people and in the boardrooms of companies with the vision to try new ways of delivering innovation. Business as usual is no longer an option.

Disclosure forms provided by the author are available at NEJM.org.

This article was published on January 18, 2017, at NEJM.org.
Source Information

From the Global Health Centre, Graduate Institute of International and Development Studies, Geneva; and the Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston.

Pembrolizumab ‘Promising’ For Advanced Urothelial Cancer

Pembrolizumab ‘Promising’ For Advanced Urothelial Cancer
Preliminary trial results support further investigation of pembrolizumab in patients with locally advanced or metastatic urothelial cancer

Date: 12 Jan 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Cancer Immunology and Immunotherapy / Urothelial Cancers

medwireNews: KEYNOTE-012 findings suggest that the programmed cell death 1 (PD-1) inhibitor pembrolizumab may be feasible for the treatment of locally advanced or metastatic urothelial cancer.

“Pembrolizumab was well tolerated in this patient population and showed an acceptable safety profile that was generally consistent with safety reports of pembrolizumab in other tumour types”, the investigators report in The Lancet Oncology.

“Additionally, promising anti-tumour activity was recorded in response to pembrolizumab.”

The phase Ib open-label study of pembrolizumab 10 mg/kg on a 2-weekly basis included 33 patients with cancers of the renal pelvis, ureter, bladder or urethra who tested positive for at least 1% programmed death-ligand 1 (PD-L1) expression on tumour cells or tumour stroma by Immunohistochemistry.

Fatigue and peripheral oedema were the most common treatment-related side effects, affecting 18% and 12% of patients, respectively. In addition, there were 11 reports of grade 3 treatment-related adverse events affecting 15% of the group and five serious adverse events affecting 9%. None of the grade 3 or serious events occurred in more than one patient.

There were four deaths in the study but none were considered to be related to treatment.

Elizabeth Plimack, from Fox Chase Cancer Center in Philadelphia, Pennsylvania, USA, and co-investigators also report activity data for 27 patients with a full assessment including at least one post-baseline scan.

After a median of 13 months, 26% of these patients had achieved an overall response, including a complete response in 11% and a partial response in 15%.

The response lasted more than 6 months in four of the patients and more than 12 months in three of the group; at time of data cutoff, one patient with a complete response was continuing with treatment and another had maintained their complete response after 2 years of treatment before discontinuing due to grade 3 hypercalcaemia.

Stable disease was the best response in 15% of patients, while 52% experienced progressive disease.

Median progression-free survival was 2 months, with 15% achieving progression-free survival at 12 months. Median overall survival was 13 months, with 50% of patients alive after 12 months, the researchers add.

“Studies with larger patient populations (KEYNOTE-052 [NCT02335424], KEYNOTE-045 [NCT02256436], and KEYNOTE-361 [NCT02853305]), including those with PDL1-negative patients, are underway to further assess the activity and safety of pembrolizumab in urothelial cancer, and to explore the association between PD-L1 expression and other potential biomarkers and clinical response in greater detail”, Elizabeth Plimack and co-investigators conclude.

The authors of a linked comment say the KEYNOTE-012 findings “add to the increasing number of studies of immune checkpoint inhibitors in urothelial cancer” and offer “a promising result when compared with the median overall survival of 6 to 9 months reported with standard salvage chemotherapy”.

But when also taking into consideration KEYNOTE-045 results comparing pembrolizumab and chemotherapy in advanced bladder cancer, they caution: “Although the survival benefit for pembrolizumab is extremely promising, it still seems that only a few patients treated with checkpoint inhibitors achieve a durable benefit with monotherapy.”

Furthermore, the study “highlights the inconsistency in the assessment of PD-L1 status as an integral Biomarker for clinical trial eligibility”, write Tracy Rose and Matthew Milowsky, from the University of North Carolina in Chapel Hill, USA.

They note that 16% of the patients who were accepted for the study based on PD-L1 positivity were later reclassified as negative by a different assay. “The findings also suggest that the inclusion of immune cell PD-L1 status might have better predictive value for response to immune checkpoint inhibitors than tumor cell staining alone”, the commentators say.

References

Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol; Advance online publication 9 January 2017. doi: http://dx.doi.org/10.1016/S1470-2045(17)30007-4

Rose TL, Milowsky MI. Checkpoint inhibition: a new beginning for urothelial cancer. Lancet Oncol; Advance online publication 9 January 2017. http://dx.doi.org/10.1016/S1470-2045(16)30675-1

PSA Nadir Heralds Increased Mortality After Localised Unfavourable-Risk Disease

Post-Treatment PSA Nadir Heralds Increased Mortality After Localised Unfavourable-Risk Disease
Prostate-specific antigen nadir at the end of treatment for unfavourable localised prostate cancer but before biochemical failure identifies men with an increased risk of all-cause mortality

Date: 16 Jan 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Prostate Cancer

medwireNews: Trial results from men with unfavourable-risk localised prostate cancer indicate that a prostate-specific Antigen (PSA) nadir above 0.5 ng/mL after treatment with radiation alone or alongside 6 months of androgen deprivation therapy (ADT) is an early warning sign of a high risk of death.

“The clinical importance of this finding is that it provides an opportunity for patient selection for clinical trial entry at a time when the patient is still responding to but has not yet [been] declared as having failed primary therapy”, write Trevor Royce, from Brigham and Women’s Hospital in Boston, Massachusetts, USA, and co-workers.

They believe this would allow such patients to “be considered for entry on to clinical trials at the time of PSA nadir investigating standard of care (conventional ADT with [a] luteinizing hormone-releasing hormone agonist) with or without novel forms of hormonal therapy (eg, enzalutamide or abiraterone) or cytotoxic chemotherapy (eg, docetaxel) that have been shown to prolong survival in men with metastatic and castrate-resistant prostate cancer.”

The researchers collated data from a subgroup of 157 men with unfavourable-risk localised prostate cancer, defined as a PSA greater than 10 ng/mL but below 40 ng/mL, or a Gleason score of at least 7, or evidence of extracapsular extension and/or seminal vesicle invasion. The patients, all of whom had minimal or no comorbidity, took part in a randomised clinical trial comparing radiation therapy with or without ADT and were followed-up for a median of 16.5 years.

This allowed the team to use the Prentice criteria for surrogacy to assess four possible surrogate endpoints for all-cause mortality: PSA failure; PSA nadir above 0.5 ng/mL; PSA doubling time of less than 9 months, and a time to PSA failure of less than 30 months.

All but the PSA failure marker met the criteria for surrogacy, giving adjusted hazard ratios for all-cause mortality of 1.72 for PSA nadir, 2.06 for PSA doubling time and 1.76 for interval to PSA failure.

And for these three surrogates, the corresponding proportion of treatment effect values, denoting what proportion of the treatment effect can be explained by the surrogate endpoint, were 103.86%, 43.09% and 41.26%.

Thus, PSA nadir greater than 0.5 ng/mL, with the value closest to 100%, was determined to be the “optimal surrogate” for all-cause mortality, the researchers explain.

Noting that PSA failure was not a surrogate endpoint for all-cause mortality even among these men in otherwise good health, the authors say this has “potential implications” for the management of patients with moderate-to-severe comorbidity after PSA failure.

Such patients might therefore be “optimal candidates for surveillance” rather than salvage ADT, they suggest, “[p]articularly given the known cardiometabolic adverse effects of ADT, which can at the very least lessen quality of life and perhaps quantity of life in such men.”

Reference

Royce TJ, Chen M-H, Wu J, et al. Surrogate end points for all-cause mortality in men with localized unfavorable-risk prostate cancer treated with radiation therapy vs radiation therapy plus androgen deprivation therapy. A secondary analysis of a randomized clinical trial. JAMA Oncol; Advance online publication 12 January 2017. doi:10.1001/jamaoncol.2016.5983