As her patients navigate between hope and fear, so does the work of Neeltje Steeghs, head of Phase
I / Pharmacology at The Netherlands Cancer Institute. New medicines, different medicines, or new drug combinations are tested at her department after promising research results at the laboratory. But the reality is usually more obstinate. Steeghs’ patients already have very poor prognoses. ‘There are no treatment options left; we may well be their very last chance. The tests they undergo are extremely demanding, with only a slim likelihood of a positive outcome,’ she says. When Steeghs applied for a job at the Antoni van Leeuwenhoek hospital in Amsterdam, she noticed that two things had been marked on her CV, and highlighted with an exclamation mark: her age (29 at the time), and her children (three). ‘“My family is now complete,” I had written next to it,’ she says, smiling. ‘The selection committee wondered where I had found the time to study medicine, work, earn a PhD, and start a family; all before the age of 29!’
Time
This is a fair observation, all the more if you glance at her now even longer CV. It seems like she has an extra hour every day; year in, year out. ‘One of the thesis statements in my dissertation was that you never lack time, but you may lack sleep! I gave birth to my youngest son during my PhD research. The day after the birth, I went back to work, straight from my bed. My baby lay in his cradle next to me. My mother called me crazy. “He’s asleep, isn’t he?” I replied. I didn’t see the issue at all.’ Neeltje Steeghs (41) lives with her husband and their three sons (12, 14 and 16) in Leiderdorp, a village in the province of South-Holland. In addition tohet work as head of the Phase I/Pharmacology department, Steeghs also works as a medical oncologist (for which she trained while doing her PhD research) and trained as a clinical pharmacologist at the Netherlands Cancer Institute. She also holds various ancillary positions in her field. Neeltje studied biomedical sciences and medicine at Leiden University. ‘I was looking for a degree program with a strong social component, and it is very important for me to use my brain,’ she explains about her choice. ‘I want to solve puzzles.’
Motivation
This same motivation also determined her decision to work in the field of oncology. ‘I didn’t want to become a GP, because I didn’t like the idea of losing my most interesting cases to the specialists. I considered a specialization in child oncology, but I was held back by the complexity of childhood cancer; I saw how parents, who made all the decisions, often pushed for more treatments than the children themselves wanted. Oncology is the most rapidly developing and most innovative medical discipline, and there is still so much to gain through research,’ she explains. The Pharmacology department mainly works on what is known as ‘Phase 1 trials’. They are currently conducting about sixty of these kinds of studies, distributed among five physicians, while a large group of specialists supervise the patients and studies. Steeghs herself leads roughly forty of these studies. ‘We’re still trying to distribute them more efficiently,’ she says, apologetically. ‘Two of the physicians have just joined us, and we didn’t want to throw them in at the deep end.’ ‘A Phase 1 trial involves testing a new drug, or combination of drugs, in humans for the first time,’ she explains. ‘At this point, you’re not so much interested in whether it works, but rather in how the drug should be administered: what dose, and at what frequency? And what are the side effects? We hope to find a dose that is tolerable, and hopefully see at least a hint of efficacy.’
Fine-tuning
Finding the right dose involves precise fine-tuning, and Steeghs continually adapts the medication to each case. She is currently leading a high-profile study that will hopefully demonstrate the logic and efficacy of customized medication programs. ‘About half of the patients right now are not getting the correct dose. That has to change,’ she says. ‘Consider the following two patients as an example. They were both getting 800 milligrams of pazopanib – the regularly prescribed dose. One patient was taking the drug for a soft tissue tumor, the other for kidney cancer. After the first two weeks, the first patient experienced so many side effects that she had to be admitted to the hospital. She turned out to have extremely high levels of pazopanib in her blood. Our first idea was to stop the tests; the risks were too high. However, this drug did offer the patients the best chance of improvement. When we persevered and reduced the dose to 200 milligrams every other day, she still had an ample concentration of the drug in her blood, but was now able to tolerate the dose.’ ‘The other patient consistently had low drug levels,’ says Steeghs, ‘so we gradually increased the dose. We eventually raised it to 1800 milligrams a day, with no further side effects The drug reached exactly the same concentration in the patient’s blood as we had seen in the other patient.’
Steeghs shakes her head when asked whether the two patients survived. ‘There’s no holy grail,’ she says. Steeghs explains why their prospects were so poor to begin with. ‘The life expectancy for patients with a metastatic soft tissue sarcomas is about twelve months. For renal cell carcinoma it’s a year and a half. Medication can prolong life and/or mitigate the effects of a disease, but without a cure, the tumor cells will at some point become resistant.’
Metastases
The patients with whom Steeghs and her colleagues work, have stage four cancer. That usually means metastases, and no chance of recovery. The Phase I/Pharmacology department can offer these people a glimmer of hope, but no more than that. ‘That makes the work really heavy. The worst are the times when I have to conclude that I have nothing more to offer a patient, especially when I have built up a long relationship with them, only to have to tell them that there are no further treatment options. I also feel terrible for the nurses, and it’s part of my job to comfort them and help them through this process.’ ‘But it’s also intense when everything does fall into place. One of our patients from Limburg has been coming here for nine years now. She gets the full treatment every time: biopsies, blood tests, medication... and all without a single problem. She inherited the breast cancer gene and takes olaparib. She has been in remission for nine years.’ ‘She lost her husband some time ago. Her son told her: “Mum, I can’t lose you too.” Her older sister, who also has the gene, was not healthy enough to undergo treatment. She has since passed away. But this woman has seen her son take his final exams, go on to university, and now she’ll be attending his wedding.’ The story of the Limburg sisters is telling; not just anyone can participate in a Phase 1 trial. ‘It’s very intensive. Biopsies, scans, blood tests, dose adjustments, the side effects, the uncertainty – only ten percent of the things that I give my patents will actually work: people have to be in good condition to withstand all that. They need to be fit enough in mind and body to make bold decisions about their own lives. They are confronted with end-of-life issues: how far do they want to go?’ ‘Yes, sometimes patients get very angry when they are not approved to participate in a trial. We have created an increasingly manufactured world, and more and more people think that life can be manufactured in the same way.’ ‘But thankfully, most of our patients are satisfied. Of course most of them hope that the experimental treatment will work, but at the same time they are well aware that it might not. People may also have a very altruistic motive: if the treatment doesn’t help them in the end, it may help others in the future. Some people are very happy just to get four extra months, while others think: this is too hard, I can’t keep doing this.’
Strictly Regulated
‘Phase 1 trials are strictly regulated, although at times, the number of safety checks is really over the top. Obviously, patients who are taking a new medicine should not become pregnant, but it makes no sense to ask a patient to take a pregnancy test every week. But we have to, because if we won’t, we are liable to face a claim from the US. Or the requirement for our patients to take the new drug on an empty stomach – sometimes all the tests and safety checks at the hospital, take up to six hours; that’s asking way too much of our patients.’
‘But at the same time, the collaboration with the pharmaceutical industry has many benefits, including financial. Our researchers can’t do it all on their own;
that wouldn’t be affordable.’ Sometimes one of her own studies at the Antoni van Leeuwenhoek hospital – one that started off as a promising laboratory experiment – eventually meets with success, or even becomes a full-fledged treatment. Those wins are what keeps Steeghs motivated. ‘You know what’s gone into it and who worked on it, and you know that what we’ve discovered has real potential. That’s something we can all be incredibly proud of.’
Courtesy of Noordhollands Dagblad.