Overview

Proton therapy is a specialised radiotherapy that uses a beam of high-energy protons (small parts of atoms) instead of X-rays. It targets the tumour while preserving nearby healthy tissue and organs, which is particularly beneficial when the cancer is near the crucial part of the body (e.g., the spinal cord).¹ Currently, NHS England recommends proton beam therapy mainly for brain, head and neck cancer, and sarcomas. However, ongoing research is exploring whether proton therapy can also treat other cancers, including lung cancer. 

Despite advanced treatments, lung cancer remains one of the most common cancers worldwide, with 2.09 million cases and 1.76 million related deaths reported in 2018.² In the United States, around 85% of lung cancer patients are diagnosed with non-small cell lung cancer (NSCLC), which has an average five-year survival rate of 44% across every stage.³ Radiotherapy is the primary treatment option for NSCLC, but it is challenging to use because lung tumours are located near crucial organs.⁴

Even though radiotherapy has improved survival outcomes for NSCLC, the risk of radiation pneumonitis (a type of lung tissue inflammation caused by radiation)⁵ has also increased, as healthy tissues are also exposed to the radiation.²

Because of this, proton radiation therapy may offer an alternative treatment for lung cancer. Early clinical proton therapy trials in NSCLC have reduced radiotherapy-driven toxicity whilst improving clinical outcomes.² However, three factors should be considered to achieve a successful outcome with proton therapy: uncertainty of the proton range, inconsistency in dose delivery, and delayed temporal effects.²

Proton therapy offers exciting potential to improve care for lung cancer patients, especially those with hard-to-treat tumours. Nevertheless, more research is needed to better understand how to use it effectively and make it more widely available.

How does proton therapy work?

Photon (X-ray and IMRT) beams are used in traditional radiation therapy, where the beams pass through the entire body.⁶ As a result, tissues not related to the the tumour receive higher levels of radiation, which can lead to adverse effects.⁶

By contrast, protons are positively charged particles that can be directed through the body to release their energy at a specific location (in this case, a tumour).⁷ After reaching the target tumour, the proton beam stops – this effect is known as the Bragg Peak and results in little or no damage to the surrounding healthy tissue and allowing for more precise treatment.⁷ 

Relative Biological Effectiveness (RBE) is a concept used in proton therapy to measure how effective it is at destroying cancer cells. The general RBE for protons is slightly higher than that of photons.⁸ This indicates that protons are more effective at destroying cancer cells. Interestingly, the RBE of protons increases at the Bragg Peak (the end of their range), where it can reach as high as 2.05 ⁷– suggesting a stronger effect on the tumour. 

It is important to remember that RBE may depend on beam characteristics and types of cells,⁹ which is particularly relevant in the treatment of NSCLC. Cancer stem cells (CSCs) in NSCLC are a small group of cancer cells with the ability of normal stem cells, like self-renewal, so they are against therapies by sustaining tumour growth.¹⁰ In a 2010 study by Chang et al., protons demonstrated a better ability to eliminate CSCs than photons.¹¹ These results suggest that proton therapy may help reduce the issues related to resistance and cancer relapse, but additional research is still needed. 

How to deliver proton therapy in clinical settings 

Two types of particle accelerators can be used to deliver a sufficient proton beam for therapeutic purposes:

• Cyclotron: delivers a continuous beam, and the beam intensity is higher¹²
• Synchrotron: accelerates protons in controlled pulses, allowing the energy of each pulse to be adjusted.¹² This flexibility helps direct the proton beam to different tumour depths¹²

These accelerators generate mono-energetic beams, meaning the energy must be reduced to reach different depths within the affected tissue.⁷ The energy selection system (ESS) in proton therapy reduces and adjusts the initial beam to produce distinct and lower energies, allowing the beams to reach various tissue depths.¹³

Regardless of the accelerator type, the beam is delivered through a treatment nozzle on a rotating gantry, accurately aimed at the tumour from different angles while the patient lies on a movable treatment couch.¹⁴ The treatment couch can be adjusted in different directions to help position the patient in the best possible way, reducing radiation exposure to nearby healthy tissue.¹²

For cancers near organs-at-risk (OARs), such as lung cancer,¹⁵ pencil beam scanning (PBS) of proton therapy is especially useful in protecting nearby critical organs (e.g., the heart) due to its three-dimensional conformality, particularly when using posterior and lateral beam angles.¹⁶ PBS has also been shown to reduce tissue toxicity in the lungs.¹⁵

What are the advantages and disadvantages of proton therapy? 

Proton therapy has the potential to improve clinical outcomes in both early-stage and locally advanced non-small cell lung cancer (NSCLC).¹⁷ Several studies have shown the advantages of proton therapy in NSCLC.  These advantages include:

• Improved survival rates in NSCLC patients, particularly significant in stage II and III cases, as shown by multivariate analysis¹⁷
• Normal tissues receive less radiation, which may allow or higher dosing and an increased chance of cure¹⁸
• Pencil beam scanning (PBS) offer better dose conformity. Its three-dimensional method delivers radiation that conforms to the tumour’s shape, even if it is complex¹⁹
• PBS also provides enhanced motion control: lung tumours move as a person breathes, and PBS has an advanced motion capture ability.¹⁹ This helps maintain treatment accuracy even with respiratory motion, a significant challenge in lung cancer radiotherapy¹⁹

However, proton therapy also has notable drawbacks: 

• Proton therapy is more expensive than traditional radiation due to higher equipment cost and setup costs¹⁸
• RBE of proton therapy is higher at the end of the beam delivery,⁷ potentially resulting in a higher-than-intended dose to nearby organs at risk²⁰
• The behaviour of protons strongly depends on what materials they pass through.²¹ As a result, tissue densities must be taken into account during proton therapy planning, though it can be dificult to measure²¹

It is also important to note that, to date, there is no prospective clinical evidence conclusively proving that proton therapy is clearly better than photon therapy.²² However, there is a strong reason to expect future prospective evidence, as many studies have already shown promising results for proton therapy.²²

FAQ’s

Are there adverse effects of proton therapy for lung cancer?

Proton therapy may cause adverse effects, but is less severe than conventional X-ray radiotherapy (photon).²³ Adverse effects associated with proton therapy include fatigue, nausea, and low blood counts, which can happen during and after treatment²³ (generally within six months after the treatment.²⁴ The probability is still lower, but proton therapy may develop pneumonitis in extreme cases.²⁴

Is proton therapy painful?

No, proton therapy is not painful because proton therapy is not an invasive treatment.²⁵

Who is eligible for proton therapy? 

In the United Kingdom, eligible patients should be:

• Stage II to IIIB NSCLC or stage IV with a single brain metastasis²⁶
• Or a recurrent tumour after surgical resection that can be treated with chemoradiation²⁶

Note: eligibility for proton therapy may differ from country to country. 

Can I combine proton therapy with other treatment?

Yes, proton therapy can be combined with photon therapy (proton-photon plans) for NSCLC patients.²⁷ In Japan, proton therapy has been used with a carbon-ion beam for a superior dose distribution to the target.²⁸

Other than proton therapy, what are the available treatments for NSCLC?

The treatment of NSCLC varies from disease progression.

• Early stage (Stages I – IIIA)
  • The most preferred treatment is surgical removal of the tumour if the patient is fit for surgery²⁹
  • Less extensive surgery is possible if the patient’s existing health condition is too risky to undergo a surgical removal²⁹
  • Stage II of NSCLC is where patients can get radiation therapy, but radiation therapy alone is not recommended to patients with N1 lymph node involvement who have already undergone surgery because it does not improve survival²⁹
  • Patients can get chemotherapy with radiation if surgery is impossible²⁹ 
• During locally advanced stages (IIIA and selected IIIB), surgery and platinum-based chemotherapy are primary treatments; radiation may prevent the recurrence of the tumour²⁹
• If the patient has N2 lymph node involvement and is in stage IIIA3 or IIIA4, chemotherapy is the first-line treatment²⁹
• Most patients in stage IIIB get chemotherapy and radiation at the same time²⁹

What are other ttypes of lung cancers in general? 

NSCLC is the most common lung cancer, but there are also other lung cancers, such as small cell lung cancer and adenocarcinoma (a subset of NSCLC).³⁰

Summary

Proton therapy is a specialised radiotherapy that uses charged proton particles to treat cancer. It is precise as its high doses are directly delivered to the tumour, minimising damage to surrounding healthy tissue. This feature is crucial for cancers near organs at risk, such as lung cancer.

In lung cancer, proton therapy has shown promising outcomes in reducing the toxicity of surrounding tissues and improving survival rates. In particular, pencil beam scanning (PBS) has enhanced dose conformity, motion management, and the possibility of safely escalating treatment doses. Several studies have shown improved survival rates in stage II and III non-small cell lung cancer (NSCLC) patients who receive proton therapy, although definitive prospective clinical evidence is not yet available. 

Proton therapy is more expensive than conventional radiotherapy due to the mandatory advanced infrastructure, like cyclotrons or synchrotrons. Planning is important for proton therapy, including consideration of respiratory motion, uncertain proton range and movement, and tissue density. Despite higher costs, lack of clinical evidence, and technical challenges, proton therapy is a promising treatment for lung cancer, as it has significant potential as an alternative. More research is required to facilitate the accessibility and practical adoption of proton therapy.