Tumour hypoxia occurs when cancer cells lack oxygen, and is associated with decreased effectiveness of radiotherapy treatments. One way to counteract hypoxia is to increase the dose of radiation we use to kill cancer cells, a technique called dose escalation. However, many side effects have been reported due to surrounding organs being damaged by off-target radiation.
Researchers at the Paul Scherrer Institute in Switzerland, led by Dr Giovanni Fattori, have been investigating the clinical potential of hypoxia-guided radiotherapy with protons in advanced-stage lung cancer treatments.
Read the original paper: https://doi.org/10.1186/s13014-021-01914-2
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Hello, and welcome to researchpod.
In today’s episode, we will be talking about how to adapt radiotherapy treatments to account for biological differences between individual cancer patients and improve clinical outcomes. Researchers at the Paul Scherrer Institute in Switzerland, led by Dr Giovanni Fattori, have been investigating the clinical potential of hypoxia-guided radiotherapy with protons in advanced-stage lung cancer treatments.
Tumour hypoxia occurs when cancer cells lack oxygen. It happens when a tumour grows rapidly in an uncontrollable manner, and/or the vasculature structure in the tumour is abnormal, so some regions are left with insufficient blood supply. Oxygen levels in cells affected by this low blood supply then drop dramatically. This condition is known to be prevalent in solid tumours and is unfortunately associated with decreased effectiveness of radiotherapy treatments. To this day, tumour hypoxia is a challenge; usually, patients affected have a very poor prognosis. In fact, hypoxic tissue is known to induce an aggressive phenotype linked to increased metastatic potential and limited efficacy of therapies. One way to counteract hypoxia is to increase the dose of radiation we use to kill cancer cells, a technique called dose escalation. Indeed, such dose escalation approaches have been investigated in clinical trials with conventional radiotherapy using X-rays. However, many side effects have been reported due to surrounding organs being detrimentally exposed to increased off-target radiation. Therefore, new ways are needed to calibrate the amount of dose escalation to each patient and precisely target treatments to the hypoxic tissue.
In contrast to these conventional X-ray treatments, proton therapy offers a higher degree of treatment conformity, meaning that high-dose radiation can be deposited precisely in the tumour region, minimising the involvement of surrounding healthy tissue. Therefore proton therapy could be an alternative for treating tumors associated with hypoxia with dose escalation. Dr Giovanni Fattori’s research team examined how to calibrate dose escalation from biomedical imaging and used radiobiological modelling of tumour response to proton radiation to estimate the clinical potential of hypoxia-guided therapy.
Fattori’s team, from the Center for Proton therapy at the Paul Scherrer Institute, in collaboration with colleagues in Maastricht, investigated the use of positron emission tomography imaging, in short PET, to quantify the level of hypoxia and, based on that, designed patient-specific dose-escalated treatments using proton therapy. Their research focused on patients suffering from non-small cell lung cancer. Non-small cell lung cancer is a subcategory of lung cancer, which is responsible for 80% of all lung cancer cases reported.
In their research, the group aimed to test an escalated dose protocol to determine whether it would be beneficial for patients and safe for use in the clinic. The clinical safety of the radiotherapy treatment is very important, since some organs, including the lungs, heart, and oesophagus, are extremely sensitive to radiation. Therefore, it is crucial that the proton dose is delivered only to the tumour tissue. If the proton dose reaches healthy cells, potentially dangerous side effects could develop. To do so, they selected a database of ten patients with non-small cell lung cancer, from an ongoing phase 2 randomised clinical trial.
Previous research studies have focused on boosting the dose either by an empirical amount or by escalating the dose as much as possible until normal tissue is damaged. The research group proposed an alternative to uncontrolled escalation, prioritising the safety of the patient. They investigated a calibrated dose escalation, which was personalised and individually tailored to each patient. First, they obtained results from PET scans performed on all patients and from that quantified the extent and location of hypoxic cancer tissue. With this information, they adapted the radiotherapy dose to control the tumour, using selective escalation where necessary, but without adversely affecting normal tissue cells. This escalation approach employed cutting-edge knowledge of the biological effects of proton radiation on human tissue and the increased radioresistance of hypoxic cells compared to well-oxygenated ones.
The researchers used many different computational methods to predict how patients would respond to the therapy while accounting for the risk of side effects. Specifically, they used predictive models to assess the probability of tumour control and the likelihood of complications in normal tissue. The combination of the above-mentioned parameters helped the researchers to prepare personalised treatments tailored to each cancer patient, and compare their approach with conventional options. The researchers report that when performing biologically driven dose-escalation with proton therapy, there is the potential for a substantial reduction of toxicity in at-risk organs, compared to conventional radiotherapy using X-ray. Significantly, they reported more than a 10% of reduction in the modelled risk of pneumonitis, about a 7% reduction in patient mortality due to heart failure, and a similar reduction in esophagitis for most patients in this study.
One concern, when using proton therapy for the treatment of lung cancer, arises from organ motion as the patient breathes during treatment, which compromises the precision of dose painting. In a recent study, the researchers weighed the decrease in proton treatment effectiveness caused by organ motion against the potential benefits of a hypoxia-targeted dose escalation. They included time-resolved four-dimensional imaging to simulate specific techniques for the treatment of lung cancer, ranging from apnoea radiotherapy to the use of monitoring to synchronise therapy with the respiratory motion, and possibly adapt during treatment to follow the position of the tumour while the patient breathes freely. Based on extensive treatment simulations, the researchers confirmed the expected benefit of targeting hypoxia with protons, with its advantages in terms of tumour control resulting from the increased dose outweighing motion-induced losses. In addition, they predict a substantially reduced risk of treatment-related complications in the lungs, heart and oesophagus compared to conventional radiotherapy methods.
The use of protons offers an opportunity for biology-driven radiotherapy treatments that move away from the one-size-fits-all approach to target individual patient conditions, this strategy being compatible with the general paradigm of precision medicine. As shown in these case studies on hypoxic non-small cell lung cancer, compared to conventional radiotherapy, personalised therapies have the potential to improve the probability of controlling the disease while minimising the risk of adverse side effects. Further trials will be needed to support the evidence in a clinical setting before widespread adoption, but the researchers are convinced of the role of biological adaptation in improving the safety and effectiveness of aggressive and radioresistant tumour treatment in the future.
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