Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management
Gaining Ground In The War On Cancer
Pancreatic cancer is notoriously difficult to detect at an early stage. A new biomarker could help to detect it early. Credit: Sebastian Kaulitzki/Science Photo Library/Getty
Nearly one in six deaths globally each year is the result of cancer. While much progress has been made in preventing, screening, diagnosing and treating this complex, varied and challenging disease, there is still far to go.
In accordance with its founding principle of Saisei-Kyumin ("to save people everywhere"), the Nippon Medical School is dedicating much of its research expertise to study cancer prevention and treatment.
As Japan's oldest private medical school, established in 1896, the Tokyo-based institute has long distinguished itself as a research facility that brings the very latest technologies to bear on medical research challenges.
Nippon Medical School has tried to develop novel medicines with both sides of basic and clinical medical sciences.
Catching a killer early
One example is the work being done by Kazufumi Honda, a professor in cancer research, to identify biological signatures of early-stage pancreatic cancer. Pancreatic cancer is one of the most deadly cancers, as by the time it is diagnosed, the disease is typically well advanced. Its symptoms include weight loss, loss of appetite, abdominal pain and changes in bowel habits. But since these symptoms are both vague and common in the general population, pancreatic cancer is hard to uncover.
If it is diagnosed at stage I, before the cancer has spread beyond the pancreas, patients have a five-year survival rate of nearly 50%. But if it's diagnosed at stage IV, the five-year survival rate slumps to 1%.
Honda and his colleagues have used an approach called proteomics — the study of the behaviour of proteins in the body — to help develop a non-invasive diagnostic test for early-stage pancreatic cancer. Using an analytic technique called mass spectrometry, which enables a detailed analysis of all the molecules in a sample, they identified key differences in the levels and activity of proteins between patients with pancreatic cancer and healthy controls.
Plasma samples for biomarker development.
In particular, they looked at a type of protein called apolipoprotein A2, and found that cancer patients process this protein differently to controls. These differences were also seen in people who didn't have pancreatic cancer, but were at high risk of the disease because they have a condition known as intraductal papillary mucinous neoplasms.
This suggests that analysing levels of this biomarker could be used to screen people for early-stage pancreatic cancer and identify those at high risk of developing it. These people could then be examined more closely using imaging technology, which is accurate but expensive.
"To efficiently establish pancreatic cancer screening in the general population, we have to identify pancreatic cancer high-risk people from the general population by using this minimally-invasive biomarker," Honda says. Having been approved by the Japanese government for in vitro diagnostics, the test will soon be available for clinical use.
Hard-to-reach tumours
Early detection is one of the pillars of cancer research. Treatment is another. In the case of lung cancer, there are numerous forms of chemotherapy, but patients often have to undergo surgery to remove the tumour, which can include removal of a section of lung. This can have long-term effects on lung function, and can be particularly risky for older patients, those with pre-existing lung disease, or those with heart disease.
A less invasive option is photodynamic therapy, in which the tumour is infused with a light-sensitive medication, then treated with lower-powered laser therapy that activates the medication and destroys the tumour. This works well for tumours in the central part of the lung because this region is relatively easy to reach with the laser using a bronchoscope that is fed down the main airways. But so far it hasn't been possible to use this approach for smaller tumours that are deeper in the lung, because they can't be reached using a traditional bronchoscope.
Jitsuo Usuda (left), Akihiko Gemma (centre), and Kazufumi Honda (right).
Now, bioengineer Jitsuo Usuda and his colleagues have developed a way to reach these small peripheral tumours using a new type of flexible laser probe. Not only is the probe able to reach deeper into the lung, but the laser frequency used is better at penetrating to the heart of the tumours.
The first clinical trial of this approach in 7 patients with peripheral lung cancer has shown promising results. An investigator-initiated clinical trial of photodynamic therapy for peripheral type lung cancer was conducted on 54 patients to apply for approval. This study was conducted on patients who were refractory to surgery or radiotherapy, and it is currently under follow up for the primary endpoint of progression-free survival.
Usuda says the treatment could mean some patients with small, early-stage cancers might be able to avoid surgery altogether. "The important thing is to maintain the quality of life and preserve the lung function, so non-invasive treatment is needed for lung-cancer patients," he says.
To understand the effect of treatments, researchers look not just at what happens to the patient's body but also the biochemical changes taking place inside the tumour and what those changes mean in terms of treatment outcomes.
A valuable resource
Minimally invasive blood tests for a biomarker for pancreatic cancer could help to detect the cancer earlier. Credit: Jasmin Merdan/Moment/Getty
This is where Nippon Medical School's rebiopsy bank becomes vital. Set up by the school's president and oncologist, Akihiko Gemma, this tissue bank stores consecutive samples taken from tumours before, during and after treatment. The hope is that by collecting these tissue samples using special systems with accurate and detailed clinical data, researchers can use them to understand how tumours change in response to treatment, how they might develop resistance to treatment, and how that resistance might be overcome with other treatment approaches.
Established in 2013, the rebiopsy bank now has more than 9,600 tissue and blood samples from Japanese patients with colorectal, lung and blood cancers. These samples have been used by a network of basic and clinical researchers to explore issues such how circulating cell-free DNA can be detected in the blood of patients with colorectal cancer, or what role non-coding RNA plays in the resistance, spread and recurrence of lung cancer.
"Our aim is to shed new light on cancer treatment," says Gemma. "And we're seeking to do this by developing therapies such as immunotherapy that lead to the prevention and control of treatment resistance."
Interstitial Lung Abnormalities In Patients With COPD Linked To Cancer, Heart Failure Risks
Interstitial lung abnormalities (ILAs) in patients with chronic obstructive pulmonary disease (COPD) are linked to lower lung adenocarcinoma rates but higher rates of other cancers and heart failure.
Interstitial lung abnormalities (ILAs) are associated with various comorbidities in patients with chronic obstructive pulmonary disease (COPD), particularly lung cancer, according to a study published in BMC Pulmonary Medicine.1
Although COPD diagnoses typically rely on patient-reported symptoms and pulmonary function tests, chest computed tomography (CT) imaging is often used to further characterize the disease and associated comorbidities.2 COPD frequently coexists with various comorbidities, like cardiovascular disease, lung cancer, and diabetes.3
Chest CT scans can also detect and characterize ILAs, incidental non-dependent abnormalities that affect at least 5% of lung parenchyma in patients without suspected interstitial lung disease (ILD).4 Previous studies linked ILA with a heightened risk for various pulmonary morbidities, like COPD and lung cancer.1
Despite the well-established relationship between ILA and respiratory morbidities, its correlation with non-respiratory comorbidities remains unexplored. Consequently, the researchers aimed to assess the association between the presence of ILA in patients with COPD and their comorbidities, along with their clinical and laboratory characteristics.
Interstitial lung abnormalities (ILAs) in patients with chronic obstructive pulmonary disease (COPD) are linked to lower lung adenocarcinoma rates but higher rates of other cancers and heart failure.Image Credit: Peakstock - stock.Adobe.Com
They examined a retrospective cohort of patients hospitalized with COPD at the First Affiliated Hospital of Xiamen University. Eligible patients were those diagnosed with COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and were hospitalized between January 2015 and August 2021.
The researchers extracted all data on eligible patients from their medical records. Next, they classified patients based on the presence or absence of ILA. Then, the researchers performed analyses to identify differences in demographic characteristics, clinical profiles, laboratory results, and comorbid conditions between the 2 groups.
The study population consisted of 1131 hospitalized patients with COPD, with males comprising 93.7%. Of these patients, 82.3% were hospitalized due to acute exacerbations, and 60% had respiratory infections; the median hospitalization duration was 8 days. Additionally, 85.6% (n = 962) had emphysema, and 14.6% (n = 165) exhibited ILAs. The 3 most prevalent comorbidities were lung cancer (19.3%), history of tuberculosis (12.7%), and coronary artery disease (9.9%).
After stratifying the study population into groups based on ILA presence, the researchers noted no statistically significant differences in clinical, demographic, or laboratory parameters. However, the one exception was circulating fibrinogen (FIB) and procalcitonin (PCT) levels. Compared with those without ILA, patients with ILA displayed significantly lower levels of FIB (3.82 g/L vs 4.34 g/L; P = .018) and PCT (0.046 ng/mL vs 0.064 ng/mL; P = .005).
Similarly, the researchers found significant differences in the prevalence of several comorbid conditions among patients with and without ILA. In particular, the incidence of lung cancer among those with ILA was about half that of those without ILA (11.5% vs 20.6%; OR, 0.50; 95% CI, 0.30-0.83; P = .006).
Of those with comorbid lung cancer, 198 were diagnosed during hospitalization, and 20 had a prior diagnosis. The researchers found that 8.6% (n = 17) of the patients diagnosed during hospitalization also had an ILA, a rate comparable to that observed in the group diagnosed before hospitalization (10%). Additionally, they further examined the association of ILA with 3 major lung cancer subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC), and other lung cancers.
Compared with those without comorbid lung cancer, those with lung ADC exhibited a significantly lower ILA prevalence (OR, 0.32; 95% CI, 0.15-0.71; P = .005). The researchers found a similar trend among patients with COPD and comorbid lung SCC (OR, 0.48; 95% CI, 0.22-1.11; P = .09); however, this was not statistically significant. Conversely, the prevalence of ILA in patients with other lung cancer subtypes was comparable to that in patients without lung cancer.
Lastly, the researchers found that the prevalence of cancers other than lung cancers in the ILA group was significantly higher than in the non-ILA group (7.9% vs 3.6%; OR, 2.27; 95% CI, 1.16-4.39; P = .012). Similarly, they discovered heart failure was more prevalent in the ILA group (11.5% vs 6.9%; OR, 1.75; 95% CI, 1.04-3.00; P = .04).
The researchers acknowledged their limitations, including the study population consisting solely of hospitalized patients with COPD, potentially limiting the generalization of their findings. Because of the male predominance among smokers in China, most patients were male, meaning these findings may not be generalizable to female patients. However, they expressed confidence in their findings and suggested areas for further research.
"...Our study demonstrates that the presence of ILA in patients with COPD is associated with multiple comorbidities of the disease, particularly lung ADC," the authors concluded. "Further investigations are warranted to better understand these relationships and their clinical implications."
References
SBRT, CRT Radiation Therapies May Not Have Many Differences For NSCLC
Two radiation therapy techniques, SBRT and hypofractionated CRT, may not have many differences for patients with stage 1 NSCLC, but limitations matter.
SBRT versus hypofractionated CRT showed no differences in benefits for patients with stage 1 NSCLC, a study demonstrated.
Radiation therapy techniques, including stereotactic body radiotherapy (SBRT) and hypofractionated conventional radiotherapy (CRT), had no detected differences for patients with peripheral and central stage 1 non-small cell lung cancer (NSCLC).
Findings from the phase 3 LUSTRE study, published in JAMA Network, compared SBRT and hypofractionated CRT by evaluating a total of 233 patients who were randomly assigned to receive SBRT or CRT. The SBRT group included 154 patients and the CRT group included 79 patients.
A total of 64 patients had centralized tumors, which included 45 patients in the SBRT group and 19 in the CRT group, according to the study.
SBRT Versus Hypofractionated CRT for NSCLCSBRT is a type of radiation therapy that delivers beams of energy to targeted areas of the body where tumors are present, as defined by the Mayo Clinic.
"Historically, radiation therapy for [patients with] lung cancer has taken several weeks to complete and required low doses of radiation given over multiple sessions — sometimes 30 or more treatments," added Dr. Bismarck C. Odei in an email interview with CURE®. "SBRT, on the other hand, allows for a dramatic shortening of the treatment duration by delivering very high doses of radiation in a safe and highly precise way. This precision targets the tumor while sparing healthy tissue, and treatments are typically completed in five or fewer sessions."
Odei is a physician-scientist and assistant professor of genitourinary cancers in the Department of Radiation Oncology at Huntsman Cancer Institute at the University of Utah.
Similarly, he explained that hypofractionated CRT also delivers high doses of radiation, but the duration of radiation is shorter than traditional radiation therapy and requires more sessions than SBRT.
"You can think of it as a middle ground between the traditional long-course treatments and the shorter SBRT approach," Odei said. "In the LUSTRE trial, hypofractionated radiotherapy required 15 treatment sessions."
WATCH: Radiation a Curative-Intent Option in NSCLC and Interstitial Lung Disease
Although the study did not find significant differences between the two radiation techniques, Odei noted that there are still some differences.
"They differ in several ways. SBRT delivers higher doses of radiation per treatment compared to hypofractionated radiotherapy. SBRT also requires fewer days to complete the treatment course, often five or fewer sessions, while hypofractionated radiotherapy may require around 15 sessions," he explained. "Additionally, when treating tumors near vital organs in the chest, SBRT may have a higher risk of [side effects] due to the higher dose per session. With either type of treatment, care is taken to ensure that the radiation is delivered safely, considering the patient's breathing and how it might affect the location of the cancer being targeted."
Why There Aren't Many Differences Between SBRT and Hypofractionated CRTIn the study, a total of 34 local control events were observed in the patient population, with 18 in patients from the SBRT group and 16 in the CRT group. The three-year local control with SBRT was 87.6% versus 81.2% with CRT.
"The LUSTRE trial found that both SBRT and hypofractionated radiotherapy had similar effectiveness in controlling the cancer and had low rates of severe side effects. This might be because hypofractionated radiotherapy, by using larger doses per session than traditional radiotherapy, can be almost as effective as SBRT," Odei said. "Additionally, advancements in radiation technology have improved the precision and effectiveness of both treatments. As a result, the difference in outcomes between the two methods may not be as significant as previously thought. However, we need more research to fully understand the differences between these two treatment approaches because the LUSTRE trial had some limitations."
An important limitation of note was that the study had fewer patients than originally planned, Odei explained.
"A smaller sample size makes it harder to see clear differences between the treatments," he said. "Also, more than half of the patients couldn't have a biopsy to confirm their cancer because of health risks. Without biopsy confirmation, there's a chance that some patients didn't actually have cancer, which could influence the study outcomes."
According to Odei, the hypofractionated CRT used in the study worked better than what was anticipated.
Reference"Stereotactic vs Hypofractionated Radiotherapy for Inoperable Stage 1 Non-Small Cell Lung Cancer: The LUSTRE Phase 3 Randomized Clinical Trial" by Dr. Anand Swaminath, et al., JAMA Network.
"This could be due to improvements in technology and techniques since earlier studies," he explained. "Because the hypofractionated radiation treatment did so well, it affected the criteria the researchers had planned to use to determine which treatment type was better.
Because of these limitations, we hope future studies will build on what the LUSTRE researchers did to deepen our understanding of these treatment approaches."
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