Hypereosinophilia in Solid Tumors—Case Report and Clinical Review

Lung Cancer Is A Priority

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Once diagnosed, the five-year survival rate of those with lung cancer is small, less than 20% according to the World Health Organization (WHO).

In 2018, Johnson & Johnson committed to fighting the disease, launching the Lung Cancer Initiative (LCI), tasked with finding better ways to screen, prevent and intercept lung cancer, in partnership with collaborators around the world.

Early identification is vital, but lung cancer is particularly difficult to self-detect, says Mark Wildgust, PhD, vice president of Global Medical Affairs, Janssen Research & Development, LLC. Lung cancer's symptoms, such as a cough, chest pain, and reduced lung function, present late and can be overlooked. "Every year you might have a cold, flu, maybe asthma, so these are not symptoms that stand out," he explains. Currently, according to the National Cancer Institute, 57% of lung cancer patients in the US are diagnosed at a late stage, when the 5-year prognosis for survival is just over 5%.

Mark Wildgust, vice president of Global Medical Affairs, Janssen Research & Development, LLC.

The LCI is spearheaded by pulmonologist Avrum Spira,MD, MSc, who works with experts from Johnson & Johnson's pharmaceutical, medical device and consumer health sectors, and alongside outside teams of cancer researchers globally.

One of the LCI's first projects studied a cohort of more than one thousand military personnel, veterans and civilians at high risk of lung cancer to investigate how different biomarkers can improve screening and early detection, and also to help develop therapeutics to arrest or eradicate the disease.

Now, the LCI is establishing a pre-cancer genome atlas — a map of molecular and cellular changes that characterize the progression of pre-neoplastic lesions to invasive lung cancer. "The goal is find a way to identify patients early in the pre-malignant stage so that we can intervene," says Wildgust.

Unique lung cancer genes in Japan and China

Genomic research into lung cancer will have to take a global view, adds Wildgust. In Japan and China patients non-small-cell lung cancer, a common form, are significantly more likely to carry an associated mutation in the EGFR gene compared to patients in the United States and Europe, for example. The EGFR gene instructs the making of the epidermal growth factor receptor protein, which is involved in cell signalling pathways that control cell division and survival.

Japan is entering a new era in precision cancer research after the government announced it would open the Center for Cancer Genomics and Advanced Therapeutics in December 2019. The centre will be a hub for whole genome sequencing, including 64,000 cancer cases, and aims to help illuminate why some ethnic groups have differing susceptibilities to lung cancer. Meanwhile, Janssen is already sponsoring clinical trials on targeted therapies for lung cancer patients with an EGFR mutation in Japan. "There is a huge unmet need in Japan," says Wildgust. "We are focused on new and novel approaches."

In addition, the reasons for increases in lung cancer rates in some countries and not others, and particularly among women, whether genetic or environmental, need to be elucidated to better target treatments, says Wildgust. Roughly one third of lung cancer diagnoses occur in China, as well as 38% of global lung cancer deaths according to the WHO. "China is ground zero for the lung cancer epidemic," Wildgust points out. As a result, Janssen has formed a broad collaboration network with key hospitals and academic centres in China, to obtain new insights and create new drug discovery programmes. The company hopes to set up similar networks in other countries.

Janssen is also looking for collaborators to harness Japanese diagnostic pathology and radiology databases to better understand the genomic and molecular bases of early-stage lung lesions.

"We recognize that the best ideas don't come from one person, or one group, but from different types of companies and organizations," says Wildgust. "It will take collaboration to change the trajectory of this disease and make a fundamental difference in the lives of so many people."

Reiko Akizuki, director of the Oncology Department at Janssen Japan, is seeking collaborators to use Japan's rich diagnostic pathology and radiology databases to better understand the genomic and molecular foundations of early stage lung lesions.

It's also important to keep moving forward, he advises. Figures from the WHO show there are more than 2 million people diagnosed with lung cancer each year and that the disease continues to cause more deaths than colon, breast and prostate cancers combined. "It is a huge burden on people around the globe. We feel that with our expertise, and our commitment, we can make a fundamental difference working together," Wildgust says.

Prostate cancer in Japan

Alongside its lung cancer push, Janssen has also established a Japanese collaboration to tackle prostate cancer. In 2019, the company launched a prostate cancer registry with the Japan Urological Association. It will enable them to study the biology of roughly 1,000 men with metastatic prostate cancer, as well as monitor disease progression.

Treatment For Lung Cancer

Treatment for lung cancer includes surgery, chemotherapy, radiotherapy, immunotherapy and other targeted therapy drugs. People may be offered one or more different treatments depending on the stage and type of lung cancer as well as their general health.

Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 87% of cases. NSCLCs can be broken down into 2 major sub-types: adenocarcinoma (sometimes referred to as non-squamous) and squamous cell carcinoma. With recent advances in scientific evidence, treatment for these subtypes is becoming increasingly different, with the identification of mutations in tumours being of particular importance in adenocarcinomas.

Small cell lung cancer (SCLC) is less common, accounting for around 12% of lung cancers. SCLC is an aggressive cancer which spreads at an early stage and so is nearly always advanced at the time of diagnosis, leading to limited curative-intent treatment options.

Adenocarcinoma is a cancer that starts in glandular cells, for example, ones that secrete mucus. These are often found in alveoli, the tiny air sacs in the lung.

Squamous cell carcinoma is a cancer that starts in squamous cells, which are thin, flat cells that line the airways.

Surgery

Surgery for NSCLC has proven to be effective, with National Cancer Registration and Analysis Service (NCRAS) data showing that 45% of people with NSCLC were still alive 5 years post-surgery. Five-year survival rates for people with NSCLC who do not have surgery was 3%.

Over the last 10 years, surgery rates in NSCLC have doubled, from around 9% in 2006 to over 18% in 2017, exceeding the target of 17% set by the National Lung Cancer Audit (NLCA).

NICE recommends that people with non-small-cell lung cancer (NSCLC), who are well enough and for whom treatment with curative intent is suitable, should be offered a lobectomy (either open or thoracoscopic). It is encouraging that data from the National Lung Cancer Audit show that surgery rates for people with stage 1 to 2 lung cancer and a good performance status have increased from almost 52% in 2015 to almost 61% in 2017, though there does appear to be significant regional variation.

An open lobectomy (thoracotomy) is the removal of a lobe of the lung through a cut made around the side of the chest.

A thoracoscopic lobectomy is keyhole surgery, where a lobe of the lung is removed using several small incisions, guided by a camera. This is normally more suitable for smaller tumours.

Surgery rates for people with stage 1 to 2 lung cancer vary across the country

Overall surgery rates for NSCLC are increasing, but there is variation across the country

Chemoradiotherapy for NSCLC

For more advanced NSCLC, surgery or radiotherapy alone is often not appropriate as the cancer has spread too far for it to be possible or effective. Even for advanced cancers that have not spread too far the curative potential of radiotherapy alone is low. A chemotherapy regimen is often added to radiotherapy to control small clusters of cancer cells that have spread to other parts of the body. Additionally, many chemotherapy agents make the cancer more sensitive to the radiotherapy.

NICE recommends that chemoradiotherapy should be considered for people with stage 2 or 3 NSCLC when surgery isn't suitable or is declined.

Chemoradiotherapy for people with stage 3 NSCLC is steadily increasing. The National Lung Cancer Audit reports that 34% of people with stage 3A NSCLC and good performance status received treatment with chemotherapy and either radical radiotherapy or surgery in 2017.

Chemotherapy, radiotherapy and chemoradiotherapy

Chemotherapy is a whole-body treatment where drugs are used to kill cancer cells by disrupting their growth. For early stage cancer, it can be used to shrink a tumour before surgery, making it easier to remove or it can be used after surgery to reduce the risk of the cancer coming back.

For people with advanced lung cancer, chemotherapy can be used to stop the cancer from spreading further and help people live longer.

Radiotherapy uses high energy x-rays to destroy cancer cells to stop them growing and spreading.

Radiotherapy can be used in early stage NSCLC for people who cannot have surgery.

It can also be used after surgery if it was not possible to remove all the cancerous tissue. In late stage lung cancer, radiotherapy can be used to manage symptoms.

Chemoradiotherapy is a combination of chemotherapy and radiotherapy. This is generally offered to people with stage 2 or 3 NSCLC who are reasonably well as it can be difficult to tolerate the side effects of both treatments.

Systemic anti-cancer treatment for NSCLC

Systemic anti-cancer treatments (SACT) include all treatments that are administered to the whole body, for example chemotherapy, immunotherapy and other medicines that disrupt the behaviour of the cancer cells. These treatments are more often used to treat advanced NSCLC. Clinical trials have demonstrated that people with advanced and incurable NSCLC can benefit from SACT, delivered to improve quality of life and to extend survival.

NICE has produced a number of recommendations relating to the treatment of NSCLC using targeted SACT and in March 2019 we published 2 algorithms for the treatment of squamous and non-squamous stage 3B and 4 NSCLC.

Baseline data from the NLCA show rates of SACT for people with advanced stage lung cancer (3B to 4) who have a good performance status are increasing, from almost 63% in 2016 to 66% 2017.

The Innovation scorecard estimates report is produced by NICE and published by NHS Digital. The report shows the trend in prescribing of NICE recommended first-generation (gefitinib and erlotinib) and second-generation (afatinib and osimertinib) tyrosine kinase inhibitors, which are indicated for the treatment of adults with locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive NSCLC.

Prescribing data indicates that the second-generation medicines have become a more popular treatment choice once available. Emerging evidence suggests that the second-generation medicines may be better in terms of prolonging progression free survival.

For the last 2 years, approximately 1,700 people in England received treatment each year with one of the EGFR targeted medicines.

Treatment for small cell lung cancer

Around 30% of SCLC cases are detected at stage 1 to 3. For those detected early enough, treatment with curative intent is an option. NICE recommends that twice-daily radiotherapy with concurrent chemotherapy should be offered to people with limited-stage disease SCLC. NICE also says that surgery should be considered in people with early-stage SCLC.

The NLCA shows that treatment with curative intent for people with SCLC has increased. In 2017, 42% of people with stage 1 to 3 SCLC with PS 0 to 2 received multi-modality treatment with chemotherapy and radical radiotherapy or occasionally surgery, which is a year on year increase since 2015.

For SCLCs that are detected at a late stage, chemotherapy and radiotherapy can be used to improve quality of life and chances of medium-term survival.

NICE recommends that people with limited-stage SCLC should be offered 4 to 6 cycles of cisplatin-based combination chemotherapy and that people with extensive-stage SCLC should be offered a platinum-based combination chemotherapy.

Data from the NCLA show that the proportion of people with SCLC who receive chemotherapy has remained steady for the last few years at around 70%, which meets the NLCA's audit standard.

Changes in commissioning

Stereotactic ablative radiotherapy (SABR) is a type of radiotherapy used to treat cancers by directing narrow beams of radiation at the cancer from different angles. The tumour gets a high dose of radiation and the surrounding healthy tissues get a low dose, reducing the risk of damage to healthy tissue.

Oligometastatic disease occurs when cancer cells from the original (primary) tumour travel and form a small number of new (metastatic) tumours. SABR is not routinely commissioned for the treatment of oligometastatic disease and was selected by NHS England for the Commissioning through Evaluation (CtE), which is part of its Evaluative Commissioning Programme.

CtE enables a limited number of patients to access treatments that are not funded by the NHS but show significant promise for the future, while new clinical and patient experience data are collected. NICE is commissioned by NHS England to oversee individual CtE schemes. The updated policy which will contain a summary of the results of the CtE scheme will be published on the NHS England Specialised Commissioning document library once a decision has been made.

Combining Kidney And Lung Cancer Screening Helps Identify Tumours Before Symptoms Develop

Combining screening for lung and kidney cancers – for both of which smoking is a risk factor – could help identify undiagnosed cases of kidney cancer, say researchers as they release the results from a study showing this approach is feasible and acceptable to participants.

Early detection of cancer allows the best chance of cure using effective treatments such as surgery. The UK has recently approved a screening programme for smokers at greatest risk of lung cancer. The programme makes use of lung computed tomography (CT) scans, which build up a detailed picture of the inside of an individual's body by taking multiple x-rays.

Certain cancers, however, are relatively rare and standalone screening programmes are unlikely to be cost-effective. One such disease is kidney cancer. Kidney cancer is the ninth commonest cancer in men and 14th in women, and is largely curable if treated at an early stage. But almost nine in ten patients (87%) will have no symptoms at the stage when it is still curable.

As lung and kidney cancers share risk factors, Yorkshire Cancer Research, in partnership with experts at the University of Cambridge, established the Yorkshire Kidney Screening Trial to see whether screening for kidney cancer could take place at the same time as screening for lung cancer. The results are published in European Urology.

"Kidney cancer is curable if we catch it early enough, but it's a largely silent disease at that stage, making it very difficult to spot."

Professor Grant Stewart, University of Cambridge, Chief Investigator on the trial

"We know that smokers who are at high risk of lung cancer are also at increased risk of kidney cancer, so it makes sense to see if we can look for both conditions at the same time."

Abdominal CT scans were offered to 4,019 'ever-smokers' – that is, people who had smoked at some period in their life – aged 55-80 years old who were attending a lung cancer screening trial between May 2021-October 2022.

Of those offered the additional abdominal scan, more than nine in 10 (93%) accepted. Of these, almost two-thirds (64%) were found to have normal abdominal scans. One in five (20%) required an imaging review but no further action. 15% required further investigations at a clinical review.

One in twenty (5.3%) participants had a previously-undetected serious finding only seen on the abdominal CT scans, including kidney and other abdominal cancers, abdominal aortic aneurysms (a swelling in the artery that carries blood from the heart to the abdomen, which can be serious because they risk bursting) and kidney stones.

Professor Stewart added: "We were able to make use of an existing targeted screening study to 'bolt-on' an additional screening test. Patients were very receptive to be screened for several conditions, and this approach helped us identify serious findings in one in 20 participants that carried a real prospect of seriously threatening life span, or of having a substantial impact on their lives."

A concern with any screening programme is the identification of incidental, non-serious lesions that do not require treatment but carry the risks associated with diagnosis and treatment, create unnecessary anxiety for these individuals, and potentially divert healthcare resources away from other conditions.

In the Yorkshire Kidney Screening Trial, a quarter of participants (25%) had non-serious findings. However, because the trials was set up to allow a robust clinical review of the radiological findings and clear lines of communication with associated specialities to determine if further tests or clinics were needed, only a third of these (8.5% of participants) had incidental findings that triggered further action in the form of further clinic appointments or investigations.

A sub-study published separately also showed that those with non-serious findings did not have lasting psychological, social or financial harms.

Speaking on behalf of the trial funder, Dr Stuart Griffiths, Director of Research at Yorkshire Cancer Research said: "People with kidney cancer are often diagnosed at a late stage when treatment options are more limited. Screening people before they experience any symptoms means the kidney cancer can be found at a very early stage – enabling many people to receive life-saving treatment."

"Adding an abdominal CT to the recently approved lung cancer screening programme provides a vital opportunity to improve early diagnosis and save thousands of lives in Yorkshire and across the UK."

Dr Stuart Griffiths, Director of Research, Yorkshire Cancer Research

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