Introduction 

Liver cancer is a serious and often life-threatening disease that affects thousands of people worldwide. It represents a significant global health burden, ranking as the sixth most commonly diagnosed cancer and the third leading cause of cancer-related death worldwide in 2020.¹ Among liver cancers, hepatocellular carcinoma (HCC) accounts for 90% of cases. Sadly, the prognosis for HCC remains poor, with an average 5-year overall survival (OS) rate of around 20%.² The majority of HCC cases are associated with cirrhosis, a condition that compromises liver function and complicates treatment. One of the biggest challenges in managing HCC is locoregional recurrence, which remains the primary cause of death, while metastatic spread is relatively uncommon, even in advanced stages.³ 

Current treatment strategies vary widely, from curative approaches like surgery, liver transplantation, and ablation. However, fewer than 20% of patients qualify for surgery due to tumour size, location, or overall health, to non-curative options like chemoembolisation and radioembolisation, which offer survival benefits for intermediate stages. However, localised liver cancer radiotherapy (RT) has emerged as a valid and potentially curative alternative to surgery for various cancers. In this article, we’ll look into what proton therapy is, how it works, and why it’s becoming an increasingly preferred option for liver cancer treatment.

Understanding liver cancer

The liver plays a vital role in filtering toxins, processing nutrients, aiding digestion and preventing long-term damage from infections like hepatitis B or C. Excessive alcohol consumption, fatty liver disease (NASH), or inherited conditions like hemochromatosis can lead to cirrhosis, setting the stage for HCC.⁴ 

Liver cancer, particularly HCC, is one of the deadliest and most common types of cancer worldwide, often developing in people with chronic liver disease or cirrhosis. Most people with liver cancer show no symptoms early on, making it difficult to catch the disease before it advances. When symptoms do appear, they are often nonspecific, including weight loss, abdominal pain, jaundice, or sudden worsening of cirrhosis symptoms, which further delays diagnosis. In some cases, patients may experience rare complications like tumour rupture, causing severe internal bleeding.

Liver cancer can also trigger paraneoplastic syndromes, leading to abnormal hormone production, metabolic disturbances, or skin changes.⁵ Unfortunately, due to late detection and the liver's limited tolerance for traditional treatments like surgery or radiation, survival rates remain low, with a 5-year overall survival rate of just 12%.⁶ 

Advances in imaging, screening for high-risk groups (such as those with hepatitis or cirrhosis), and emerging therapies like proton therapy are offering new hope. Proton therapy, in particular, is showing promise by delivering highly targeted radiation to the tumor while sparing the surrounding healthy liver tissue, which is a crucial benefit for patients whose liver function is already compromised. Early detection and innovative treatments are key to improving outcomes for liver cancer patients.

What is proton therapy?

Proton therapy (PT) is one of the most advanced types of radiation treatment available today. Unlike traditional X-ray radiation, which affects the tumour and surrounding healthy tissue, proton therapy delivers energy precisely to the tumour alone thanks to a unique feature called the Bragg peak. This means less damage to nearby organs like the stomach, intestines, and lungs, which is especially important when treating liver cancer.

Several dosimetric studies have confirmed proton therapy’s superiority over traditional photon-based RT in liver cancer. A 2008 study found it reduced the average liver radiation dose by 30%, lowering the risk of radiation-induced liver disease.⁷ More recent studies recommend proton therapy for liver tumours larger than 3 cm, especially those in difficult-to-treat areas like the centre or top of the liver. This is crucial because tumours over 3 cm are harder to treat with other methods like ablation. Proton therapy offers a safer, more effective alternative in these cases, improving the chance of controlling the tumour while protecting healthy tissue.⁸

Overall, proton therapy represents an exciting advancement for liver cancer treatment, offering precision, safety, and a better chance of preserving liver function, especially for patients with large or hard-to-treat tumours.

How proton therapy works for liver cancer

Proton therapy for liver cancer is a carefully planned and precise process designed to target the tumour while protecting healthy tissue. It starts with a detailed planning stage, where a team of doctors, radiation specialists, and medical physicists use advanced imaging like CT, MRI, or PET scans to map the tumour’s size, shape, and exact location in the liver. To ensure accuracy, patients may be fitted with custom moulds to keep their body still during treatment.⁹ 

During proton beam delivery, a machine known as a cyclotron or synchrotron accelerates protons to high speeds, directing them towards the tumour. The beam is calibrated to release radiation precisely at the tumour’s depth, minimising exposure to healthy tissue. Throughout the session, real-time imaging tracks the tumour’s position, adjusting the beam as needed to ensure accuracy — crucial for liver tumours, which can shift slightly due to breathing movements. Each session typically lasts 15 to 30 minutes, with patients undergoing multiple treatments over several weeks. The exact number of sessions varies based on factors like tumour size, location, stage, and patient health.¹⁰ 

Advantages of proton therapy for liver cancer

Proton therapy offers multiple advantages over conventional radiation therapy, particularly for liver cancer patients. One of the most compelling benefits is its precision, allowing doctors to target the tumour with millimetre accuracy while sparing healthy liver tissue and surrounding organs. This precision leads to fewer side effects, reducing the risk of fatigue, nausea, radiation-induced hepatitis, and liver decompensation, which is a crucial factor for patients with underlying cirrhosis.

Moreover, proton therapy supports higher radiation doses delivered directly to the tumour without increasing toxicity, which can significantly improve tumour control rates. Traditional radiation methods often limit the dose to avoid harming nearby healthy tissues, but proton therapy’s unique ability to stop precisely at the tumour means higher doses can be safely administered. This makes proton therapy particularly beneficial for patients with inoperable tumours or recurrent liver cancer, where surgery or additional conventional radiation might not be feasible due to prior treatments or the tumour’s location. In such cases, proton therapy offers a powerful non-invasive alternative, improving the chance of controlling the disease without further damaging healthy tissues.⁸ 

Possible side effects of proton therapy

While proton therapy is known for its reduced side effects compared to traditional radiation, some patients may still experience mild to moderate reactions, including:

• Fatigue - feeling tired after treatments
• Skin redness or irritation at the treatment site
• Nausea or loss of appetite - depending on the liver's condition and the radiation area
• Temporary liver enzyme changes - monitored closely by the medical team

Most side effects subside after treatment ends. Doctors provide supportive care to help manage any discomfort.¹¹ 

Proton therapy vs other cancer treatments 

Liver cancer treatment often involves a combination of therapies, depending on the cancer’s type, size, and stage.

Summary 

Proton therapy represents a transformative advancement in liver cancer treatment, offering unparalleled precision and effectiveness, especially for patients with inoperable or recurrent tumours. Its ability to deliver high doses of radiation directly to the tumour while minimising damage to surrounding healthy tissue is a game-changer in reducing side effects and preserving liver function, which is crucial for patients already battling cirrhosis or compromised liver health.

Compared to conventional radiation therapies, proton therapy significantly lowers the risk of radiation-induced liver disease, making it a safer option for those with larger or hard-to-treat tumours. Studies have consistently shown improved local tumour control and overall survival rates, reinforcing its growing role as a frontline treatment for liver cancer.

While no treatment is without side effects, proton therapy’s reduced toxicity profile ensures patients experience fewer complications, allowing for better quality of life during and after treatment. As technology continues to advance with innovations in motion management, imaging, and beam delivery, proton therapy is expected to become even more precise and accessible.

For liver cancer patients who may have limited options, proton therapy offers renewed hope, providing a safer, more effective path to prolonged survival and improved outcomes. It stands as a beacon of progress in the ongoing fight against this challenging disease.