When approximations aren’t enough – Limitations with intravascular brachytherapy

Not only has the time for personalized treatment of cardiovascular disease arrived but patient outcomes have been put in jeopardy when patient specific anatomy is not considered.

The future of medicine is in screening, prediction, early diagnosis and individually tailored treatments including post-treatment follow-up, i.e. in personalised medicine. A recent editorial in Nature Medicine discusses the scarcity of personalized medicine for treatment of cardiovascular disease while it has revolutionized cancer therapy [1]. In radiation therapy specifically, clinical research and technological advances in imaging and radiation delivery systems have enabled the capability to personalize treatments for accurate delivery of radiation dose to the tumours and limiting dose to nearby radiation sensitive healthy tissues based on clinical parameters and patient-specific anatomical information.

Due to recent insights in disease mechanisms and emerging treatment strategies, the time is opportune to develop personalized treatments for cardiovascular disease. Introducing personalized medicine for cardiovascular disease should not only be pursued as a means of improving outcomes and identifying novel treatment strategies, it must be pursued to ensure that existing treatments are appropriate and will be effective. There exists a modality of treatment for cardiovascular disease for which the absence of patient specific information is not only a disadvantage but may actually hinder successful treatment. Intravascular Brachytherapy (IVBT) is a form of radiation therapy used to treat in-stent restenosis (ISR). After the advent of the bare-metal stents in the 1990s, a new difficulty arose when sites initially treated with a stent became re-stenoted in the months following initial treatment. IVBT involves applying a dose of ionizing radiation to the arterial walls immediately after stent implantation to destroy neointimal tissue which may proliferate and lead to ISR.

It is well known that if an inadequate dose of radiation is delivered to the target area, or if the size of the target area is underestimated, the treatments may fail, and patient outcomes will be jeopardized [2]. Early attempts to implement IVBT involved coating stents with beta emitting radioactive isotopes. Treated arteries became re-stenoted on each side of the radioactive stent where the radiation dose fell off due to insufficient coverage of the radioactive isotope at the stent ends. This side effect lead to the development of catheter-based devices, where beta emitting radioactive sources (radioactive seeds) are guided temporarily to the stented site (dwell position) immediately after stent implantation and kept at the site for a certain amount of time (dwell time) until an adequate dose is delivered.

Compared to other forms of radiation therapy, treatment planning in IVBT is archaic. It consists of an estimation of the patient’s artery diameter by visual inspection under fluoroscopy and then referring to a reference sheet which lists the dwell times for different vessel diameters. This method of treatment planning assumes that the patient’s artery is a perfect cylinder, that the radioactive seeds are centered in the cylinder, and that all tissue and materials surrounding the treatment site are water equivalent.

With the advantage of modern software and computing capabilities, we have been able to revisit the underlying assumptions of IVBT. In a tank of water (which serves as a crude approximation for patient tissue), the range of beta particles from the isotopes used in IVBT is about 2 mm, which corresponds to the distance from the surface of the radioactive seed to the target region. In the water-equivalent approximation, the target region receives the prescribed dose of radiation. In a real-world delivery, the beta particles interact and are absorbed by non-water equivalent materials such as the metallic cardiac guide wire, the stent and calcifications as well as patient tissue. Recent work indicates that the cardiac guidewire used to guide the radioactive seeds to the treatment site blocks the ionizing radiation and can cause dose reductions as high as 48% in regions behind the guidewire alone [3] [4]. When the presence of arterial stent struts and calcified plaques are considered, the dose of radiation can be reduced by more than 60% in localized regions. The target volume is behind these heavily attenuating media and will not receive the prescribed dose, i.e. the delivered dose will be much less than the prescribed dose.

This all might seem inconsequential if IVBT weren’t undergoing a small revival. The use of IVBT was reduced due to the advent and adoption of drug-eluting stents (DES) in the early 2000s. However, a need for IVBT still exists. Patients treated with DES require coronary reintervention [5]. The typical modality of treatment for patients whose DES failed is to insert another DES at the initial site of stent failure. For a group of patients with multiple DES implemented at the same site IVBT has been shown to be a safe and effective treatment [6]. A need for IVBT is still being communicated by cardiologists; a 2016 editorial in the Journal of the American College of Cardiology calls for IVBT to be considered for patients with DES failure [7].

The world of medical physics can at times be separated from the world of physicians. There isn’t always adequate knowledge exchange between medical physicists and their colleagues; the concerns of physicists can seem technical and out of touch with the concerns of practitioners. This is one instance where it is important physicians have at least a rudimentary understanding of the physics underlying a treatment modality so that it can inform their practice. Cardiologists should be wary of applying current IVBT technology when they have reason to believe that large calcified plaques exist at the treatment site or multiple stents have been previously implanted, as the dense bulk material serves to block ionizing radiation from reaching the target neointimal tissue; both of these factors may be contraindications for IVBT.

If IVBT is going to see continued use, the medical community owes it to patients to ensure that device manufacturers modernize their devices and seek out solutions to the real and significant problems that have been identified with IVBT products, otherwise manufacturers will continue to produce the same IVBT devices which have been on the market for more than 15 years now. We have suggested solutions to improve current IVBT delivery systems and dosimetry [3] [4] but only if the cardiology community is informed and insists that devices allow for patient specific treatment planning, will manufacturers make meaningful changes to their products. The reluctance and concerns of a small group of informed medical physicists is not enough to prompt any change in the current practice of IVBT.

Written by Joseph DeCunha and Shirin A. Enger

[1] Nature Medicine Editorial Board. Taking personalized medicine to heart. Nature Medicine 2018; 24:113.

[2] van der Giessen WJ, Regar E, Harteveld MS, et al. “Edge Effect” of 32-P Radioactive Stents is Caused by the Combination of Chronic Stent Injury and Radioactive Dose Falloff. Circulation 2001; 104:2236-2214.

[3] DeCunha J, Janicki C, Enger S.A. A retrospective analysis of catheter-based sources in intravascular brachytherapy. Brachytherapy 2017; 16:586-596.

[4] DeCunha J, Enger S.A. A new delivery system to resolve dosimetric issues in intravascular brachytherapy. Brachyherapy 2018; article in press.

[5] Ohri N, Sharma S, Kini A, et al. Intracoronary brachytherapy for in-stent restenosis of drug-eluting stents. Adv

Overcoming Nobel Prejudice: Story of Lise Meitner and Nuclear Fission

HanMeitner

Nuclear fission is one of the most important discoveries of the 20th century. Yet not many know that it was Lise Meitner who was behind the discovery, just after her escape from Nazi Germany to Sweden in 1938. In 1944 Otto Hahn, Lise Meitner’s laboratory partner of thirty years, who remained in Berlin throughout the Third Reich, was awarded the Nobel Prize for Chemistry. The separation of the former collaborators and Meitner’s exile in Sweden led to the Nobel committee’s failure to understand her part in the work. The Nobel committee’s mistake was never acknowledged, but was partly rectified in 1966, when Hahn, Meitner, and Strassmann were awarded the United States Fermi Prize. She was also awarded numerous prizes and honorary doctorates by universities in the United States and Europe.

Who was Lise Meitner?

Lise Meitner was born in 1878 as the third of eight children of a Viennese Jewish family. She showed an early talent for mathematics and was privately tutored. Her father insisted that each of his daughters should receive the same education as his sons. Due to Austrian restrictions on female education, she entered the University of Vienna in 1901, at an age of 23. She was the first woman admitted to the university’s physics lectures and laboratories. With Ludwig Boltzmann as her teacher, she came to the conclusion that physics was her calling and earned a doctoral degree in physics in 1905. Three of her sisters also earned Ph.D. degrees later.

Meitner was invited to Berlin by Max Planck to continue with her post-doctoral studies. From 1907–1912 Meitner worked as an unpaid research scientist at the Berlin Institute for Chemistry but was not permitted access to the laboratories since women were prohibited entry to the institute. During this time she met the radio-chemist Otto Hahn, who became a thirty-year research partner in experimental work discovering new radioactive elements and unraveling their complex physical properties.

After World War I Otto Hahn was named the administrative director of the Kaiser Wilhelm Institute for Chemistry, while Meitner supervised the Physics Section, which she led successfully for over twenty years until forced to flee Berlin under the Third Reich. Meitner became an official University Lecturer in 1922, but even in liberalizing Berlin the press jokingly reported the topic of her inaugural speech as “Cosmetic Physics” instead of cosmic physics. In 1926 she was given the title of Professor.

From 1924 to 1934, the Meitner-Hahn team gained international prestige and were competing with the Paris team of the Irene Joliot-Curies and Rome’s Enrico Fermi to unravel the complexities of the mysterious “transuranic” elements. They were nominated for the Nobel Prize in Chemistry for ten consecutive years. They were also nominated for the Nobel Prize in Physics by Max Planck, Werner Heisenberg, Bohr and von Laue in 1936. Meitner was nominated for the Physics Prize three times by Niels Bohr after the World War II.

In 1938 when the National Socialists issued an order forbidding famous scientists to travel abroad, the international physics community under lead of Danish physicist Niels Bohr orchestrated Meitner’s escape route from Berlin. Her final destination was Stockholm, Sweden. Niels Bohr arranged work for Meitner at the new Nobel Research Institute of Physics under the leadership of Professor Manne Siegbahn, who won the Nobel Prize in Physics in 1924 for his discoveries in the field of X-ray spectroscopy. In Stockholm, Meitner lived on a meagre research assistant’s salary. She was neither asked to join Siegbahn’s group nor given the resources to form her own, she had laboratory space but no collaborators, equipment, or technical support, not even her own set of keys to the laboratory.According to some authors Siegbahn blocked Meitner’s research career in Sweden since he distrusted female scientists and he feared that Meitner, who was a brilliant physicist would outshine him with her ground-breaking research. Some physicist also later accused Sigebahn of having hindered her from receiving the Nobel price due to his extraordinary strong position in Swedish scientific community and membership of the Nobel committee.2

Meitner continued to exchange letters almost daily with Hahn. They met in Copenhagen in 1938 and planned new experiments. She urged him and their assistant Fritz Strassman in Berlin to continue research she had instigated on uranium. On December 24, she received a letter from Hahn recounting a strange “bursting” he described as occurring to uranium, forming barium. Hahn asked his trusted colleague to interpret this process: “What would physics say about such bursting?” He had written up their findings and submitted them to Die Naturwissenschaften on December 21 without crediting her contributions, and this act would literally eclipse Lise Meitner’s contributions to the discovery of nuclear fission in 1938.

Meitner and her nephew Otto Frisch, while hiking in the snowy Swedish woods, realized Bohr’s “liquid-drop” model of the atomic nucleus could explain the result mathematically. They scribbled formulas on a scrap of paper in the woods: A uranium atom could elongate when bombarded by neutrons, and occasionally some of the uranium atoms could split apart into two “smaller drops.” Frisch later dubbed this process “fission”, a term used by biologists to describe the elongated splitting of a cell. In fact, the uranium atoms in Hahn’s experiments had split to form the much lighter atoms barium and krypton, and ejected neutrons and a very large amount of energy, with a loss of some mass. Meitner was the first to realize Einstein’s famous equation E=mc2 was at play here, converting mass into energy. In January–March 1939, she wrote a series of articles to be published in Nature with Frisch on the nuclear fission of uranium.

In Sweden Meitner encountered concentration camp victims, which convinced her to never return to Germany, although in 1947 Hahn and Strassmann invited her to re-join them at the rebuilt Institute for Chemistry. She declined their invitation to form a new Max Planck Institute for Chemistry named after their mentor, and instead retired in Sweden on a small pension. Meitner spent most of her 70s and 80s traveling, encouraging female students to “remember that science can bring both joy and satisfaction to your life.” During her final years she lived close to her nephew Otto Frisch, in Cambridge, England, where she died on October 27, 1968.

  1. Lise Meitner: A Life in Physics, Ruth Lewin Sime, California Studies in the History of Science (11), 1997
  2. The Key to Nuclear Restraint: The Swedish Plans to Acquire Nuclear Weapons During the Cold War, Thomas Jonter, Palgrave Macmillan, 2016

Patient preferences and treatment choices for localized prostate cancer

After receiving cancer diagnosis, follows a chaotic time full of anxiety, fear and endless grief for the patients. Prostate cancer is the most common cancer amongst men in Canada and in the most cases it is diagnosed when it is still curable, nevertheless these men are faced with a long journey with many decision points along the road where they must manage their personal fear of a cancer death with the overwhelming thought of leaving their loved ones behind. In this state of mind, it is expected of the patients to get involved in the decision making process regarding their treatment.

Treatment options for localized prostate cancer are many, vary widely, and there is no consensus regarding the optimal treatment strategy. Ongoing research in the area of patients decision making and post intervention regret, reveals some insight in the patient’s choice of treatment option. Surgery is often preferred by patients seeking a cure, while brachytherapy is more often chosen by patients professing a desire for “the least invasive” treatment. Although patients stated that side effects are important, few patients report that side effect factors ultimately influence their treatment choice. However, there are several studies pointing out that men with prostate cancer often base treatment decisions on scientific misconceptions and anecdotal experiences of friends or family. Race/ethnicity and socioeconomic status plays a role as well.

Some studies show that the actual treatment choices bear little relation to the patient preferences, and instead show a strong association with clinician specialty. Physician’s advice depends heavily on the their specialty (radiation oncology vs. urology), as well as geographic region. In a recent study published in nature , researchers investigated the importance of physician’s attitudes about different treatments and the quality of life in prostate cancer, by performing a survey of specialists to assess treatment recommendations and perceptions of treatment related survival and quality of life. The conclusions from the study were that the radiation oncologists and urologists both prefer the treatment modalities they offer, perceive them to be more effective and to lead to a better quality of life. Patients receive biased information, and a truly informed consent process with shared decision making may be possible only if they are evaluated by both specialties before deciding upon a treatment course. In the absence of relevant randomized trials no decision regarding the superiority of any of the treatment modality can be made and the potential impacts of treatment side effects on quality of life for patients and their partners have to be considered in the informed decision making process.

Frustration leads to innovation

According to a report from Canadian parliamentary budget office 40% of young Canadian graduates are overqualified for the work they do. There is obviously a mismatch for graduates between their skills and opportunities that leave them with high debt and low incomes. The keys to reverse the trend are industry-university partnerships, jobs-oriented training and greater counselling and guidance to prospective university students in choosing their field of study. However, the Internet is full of innovations born from frustration. I hope that the disappointment and frustration of being overqualified will not just result in despair, but in a new wave of innovative entrepreneurs.