Targeted radiotherapy for lung cancer is a promising reveal?

What is Targeted radiotherapy for lung cancer?

Targeted radiotherapy for lung cancer uses high doses of ionizing radiation to kill cancer cells. This is a novel treatment method for many types of cancers including lung cancer. It damages the DNA of cancer cells and kills them. Then it shrinks the tumours. And this blocks the growth and development of tumours. This approach has overcome many of the blockages of conventional therapies for lung cancer. For instance conventional radiotherapy and chemotherapy. 

Why targeted radiotherapy for lung cancer but not just radiotherapy?

Targeted radiotherapy for lung cancer has high specificity and selectivity. It targets only the cancer cells instead of damaging surrounding tissues. In contrast, conventional radiotherapy can damage nearby tissues as well by passing radiation to them also. To clarify, current available conventional therapies and anticancer agents destroy groups of cells that have uncontrolled growth. The treatments mainly focus on nonspecific cell division. Hence they damage the rapidly dividing non-tumour cancer cells. Ultimately causing lots of side effects,

Instead targeted radiotherapy for lung cancer selectively identifies the cancer cells. They are designed to work like that. It uses computer technology to get a 3D image of tumour cells. It specifically targets cancer instead of surrounding cells. Moreover, this is a 3D conformational radiotherapy. Thus targeted radiotherapy for lung cancer is quite different from normal conventional radiotherapy.

Ultimately, targeted radiotherapy for lung cancer provides a better outcome without causing many unwanted side effects.

Does targeted radiotherapy work for lung cancer?

Radiotherapy is an effective treatment for lung cancer. During the past decades about half of all cancer patients including lung cancer have received radiation therapy or radiotherapy. They have increased their survival time significantly.

Among the different treatment procedures targeted radiotherapy for lung cancer can effectively provide positive outcomes. In terms of survival, reducing tumour cell growth and development, effective drug delivery, and fewer side effects targeted radiotherapy for lung cancer is becoming a hope for cancer patients. In addition, personalized medicine plans based on an individual’s targeted approach have positive results even though it is now in preclinical and clinical settings.

What are the optimal radionuclides used in targeted radiotherapy for lung cancer?

A radionuclide is an atom or particle with an unstable nucleus. It emits gamma rays, X-ray photons, and positrons and becomes stable. Also, it has another name “radioisotope”. According to research named “Advancing Nuclear Medicine Through Innovation” which was published in 2007, there are three types of radionuclides used in targeted radiotherapy for lung cancer.

Alpha emitting radionuclides

An alpha-emitting radionuclide has a size that fits into a few cell diameters. In other words, because of its smaller size, it can effectively target the appropriate cancer cells. It has proven. Moreover, it possesses high linear energy transfer thus alpha-emitting radionuclides show greater effectiveness when targeting cancer cells. This is relative to the conventional external beam X-ray radiation and beta-emitting radionuclides.

Other than that, studies using cell cultures have shown even a few alpha particles can kill cancer cells. Unlike other radiation types, alpha particles can effectively remove cancer cells even when oxygen is not available. To clarify, other radiations need oxygen to create free radicals.

Although with all of these successes, usage of alpha particles in targeted radiotherapy for lung cancer is still in clinical trial phases. However, the studies are ongoing, and hopeful future results will come up soon.

Beta – emitting radionuclides

Currently, the US FDA has approved only four types of beta-emitting radionuclides in targeted radiotherapy. They are,

  • yttrium-90
  • Iodine-131
  • samarium-153-EDTMP
  • Strontium-89-chloride

However continuous preclinical and clinical trials are useful to evaluate new beta particles.

Auger Electron-Emitting Radionuclides

  • Bromine-77
  • Indium-111
  • Iodine-123
  • Iodine-125. These Auger Electron-Emitting Radionuclides are currently under investigation.

Auger Electron-Emitting particles emit Auger electrons when they decay by electron capture. The Auger Electrons (AEs) are very low-energy electrons.

Studies in cell cultures have proven they have excellent properties in targeting and specific tumour cell killing. The novel combination therapies radionuclides with molecular carriers allow more reliable tailored medication plans for individual patients.

How does targeted radiotherapy for lung cancer perform its activity?

Targeted radiotherapy for lung cancer does work by using a molecular vehicle to deliver the radiation to the tumour. When the patient gets the drug by injection it transmits through the blood to the target. The radionuclides are attached to tumour searching molecules. Those molecules can find specific targets on cancer cells. Usually, they are on the surface of the cancerous tumours or within the tumour. Monoclonal antibodies or their fragments are the targeting agents for many tumours.

Unlike conventional radiation therapies targeted radiotherapy for lung cancer has a “bystander” or “crossfire” effect. It is a unique feature of radionuclides. To put it another way, radionuclides can destroy nearby cancer cells even if they lack tumour-specific receptors or antigens.

The particles used in targeted radiotherapy for lung cancer must emit radiation in a relatively short pathway. There are three main types of radionuclides in targeted radionuclide therapy which are alpha emitters, beta emitters, and auger-electron emitting radionuclides.

In addition, therapists can use combinations of radionuclides for both imaging and treating the tumours at once. For instance the mixed beta/gamma emitter iodine-131.

In essence, the variety of tissue ranges, half-lives, and chemistries of radionuclides provide great opportunities to find new therapies in targeted radiotherapy for lung cancer. This is especially for individual treatment plans in precision medicine.

What are the advantages of Targeted Radiotherapy?

  • Unlike normal conventional radiotherapy, targeted radiotherapy directly targets only the cancer cells.
  • It provides less harm to normal healthy cells.
  • This provides the opportunity to create medicines with a high therapeutic index that has minimal health risks.
  • Targeted radiotherapy has high patient compliance.
  • Administration of Targeted radionuclide therapy needs a very short time. Likewise, the effect of radionuclides starts within a short time. Therefore patients do not need to go for treatments like traditional methods.
  • No need of getting unnecessary additional treatments within the period of targeted radiotherapy for lung cancer.

How successful is targeted radiotherapy for lung cancer?

Thousands of new anticancer treatments are currently in different phases of clinical trials. Among them, targeted radiotherapy is only one type of targeted therapy. This approach is useful not only for lung cancer but also for other types. For example breast cancer and brain tumours.

Although the targeted radiotherapy for lung cancer is still not very common in clinical usage, it has significant improvement in the success rate. According to some research, the success rate of targeted radiotherapy for lung cancer maybe 85% to 95%. Therefore it is immensely effective for lung cancer.

What are the differences between external beam radiotherapy and targeted therapy for lung cancer?

External beam radiotherapyTargeted radiotherapy
Uses the tumour locationUses the tumour biology
Produces more side effectsProduces fewer side effects
Less selectivity than targeted radiotherapyHigh selectivity
Less effective because mainly focus on tumour locationDesigned to destroy even small tumours hence more effective
This is not a systemic treatmentThis is a systemic treatment
A large area is affected and damaged by radiationOnly the targeted area will be damaged, other areas are not affected by radiation.
Uses high energy X-raysUses radionuclides or radiolabeled molecules designed to find cancer cells
Photons and electrons are the radio particlesRadioisotopes like beta particles, alpha particles, and auger electron-emitting particles
Has well-defined dosimetry (50Gy-80Gy)MIRD dosimetry (15Gy-30Gy)
The dose rate is about 60-120Gy/hrLow dose rate irradiation (0.1< -1Gy)
Consider tumours radiation sensitivity, microenvironmentConsider tumour size, antigen density, radiation sensitivity, and microenvironment.

How about the dose-rate effect on targeted radiotherapy for lung cancer?

The dose-rate effect of targeted radiotherapy is important in conventional radiotherapy because of its possible harmful impact on both normal and cancer cells. However, the dose-rate effect of targeted radiotherapy for lung cancer has only a partial or temporary impact. In other words, targeted radiotherapy is responsible for controlling cancer development effectively.

Important to realize the biological response for radiation therapy also depends on the dose rate. In other words, the dose delivering rate. If the radiation delivery is low the tumour cells will repair again due to SLD repair. The SLD repair stands for Sublethal damage repair. The cancer cells can recover again when the suppression is quite weak.

Until a certain limit of radiation cells can improve their survival. After that limit cell death becomes increased even in decreased dose-rate. This is the inverse dose-rate effect. Cells die because of the arrest of the G2 phase of the cell cycle which is more vulnerable to cell death.

Is targeted radiotherapy for lung cancer safe?

Yes, basically it is very safe. However, in the same manner, as other therapies targeted radionuclide therapy also have some risks. In contrast, it outweighs the benefits out of the risks. If you can have the right drug in a drug dose and at the right time you can have more benefit out of the risks of the therapy.

What are the advances of targeted radiotherapy?

Tumour necrosis targeted radiotherapy for non-small cell lung cancer

Tumour necrosis treatment (TNT) is a kind of developing targeted radiotherapy for lung cancer. It is a type of tumour-targeted radiotherapy. During recent times anticancer treatments focus has shifted from normal chemotherapies towards targeted therapies. Tumour necrosis-targeted radiotherapy is another new advance for NSCLC which is tested in mouse models.

With the development of radiotherapy 3-dimensional conformal radiation therapy or targeted radiotherapy for lung cancer and other types has become vital.

However, tumour-targeting therapy is somewhat difficult because of certain obstacles.

  • Techniques like 4 dimensional CT scanning for imaging and other advanced techniques suitable for locoregional treatments. They are not very suitable for systemic therapies. For instance patients with metastatic diseases, these methods provide less curative results.
  • Safe delivering problems of biologically effective doses for targeted radiotherapy for lung cancer. This is because of the possible harm to the normal tissues while delivering the drug to the tumor.

TNT uses monoclonal antibodies which target universal antigens within the dying cells of the tumours. These dying cells are the necrotic cells. This is more suitable for necrotic regions of the tumours.

The combination of the TNT method is using radionuclides combined with monoclonal antibodies. This pair can deliver the drug to the appropriate site of the tumour. Then they emit radiation and kill cancer cells or block their further development.

According to a publication on Oncotarget in 2015, China has approved the use of Iodine-131 radiolabeled chimeric tumour necrosis therapy monoclonal antibody (131I-chTNT) for advanced lung cancer.

However certain bad effects have limited the application. For example

  • macromolecule immunogenicity of monoclonal antibodies
  • Bone marrow suppression.

What is immunogenicity?

Immunogenicity is the ability of antibodies to start an immune response in the body. This can be in humans or other animals.

How Tumor Necrosis Treatment overcomes the immunogenicity problem?

A substitution of small necrosis-targeted molecules can solve this problem effectively. Recent studies in the advancement of preclinical development of tumour necrosis targeting agents have proven results in Tumor Necrosis Targeted radiotherapy for lung cancer as well as other cancer types. TNTR provides a novel treatment method, especially for NSCLC patients.

In addition, there is a tumour vascular disrupting agent (TVDA) known as Combretastatin-A4-phosphate (CA4P). This leads to successful, rapid, and extensive damage to the blood vessels of the tumour. Accordingly, without the blood vessels, tumours cannot get nutrition or oxygen and survive. Therefore they should definitely go for death. First, they become ischemic or lack blood supply, and thereafter necrosis or cell death happens.

These necrotic sites of the tumours become suitable targets for necrosis-avid agents. In summary, a combination of radionuclide labelled necrosis-avid agents with a VDA provides a summation activity in TNTR.

What about the targeted radiotherapy for lung cancer in early-stage patients?

Immunotherapy with targeted radiotherapy may increase the survival time of early-stage lung cancer patients

According to the publication in the Lancet Oncology, 17 May 2021, patients with early-stage NSCLC have shown a quick response to a combinatory therapy. They have used neoadjuvant Durvalumab with stereotactic body radiotherapy. Fortunately, this has shown positive results than just using immunotherapy alone.

In this study patients suffering from early lung cancer have received an immune checkpoint inhibitor and foal or targeted radiotherapy for a short time. At the final of the study, they showed a significant increase in response. In other words, the treatment could kill at least 90% of cancer cells.

The study was a single-centre phase 2 trial with 60 adults who have stage 1-3A NSCLC. They grouped those patients into two groups. One group received neoadjuvant Durvalumab alone and the other group received neoadjuvant Durvalumab with stereotactic body radiotherapy.

 Figure No.01: patient grouping in the study.

This was an unblinded study after the randomization. After That patients received two 60-minute cycles of 1.12g intravenous infusion of Durvalumab for three weeks. Patients in combination therapy received three consecutive daily fractions of stereotactic body radiotherapy. They received each radiotherapy fraction of 8Gy to the primary tumour.

Figure No.02: progression results from the patients who participated in the above study. Among patients in both groups, 13.0% showed disease progression and 87.0% didn’t show any progression. They needed to have surgery.

Figure no.03: percentage of patients who showed major pathological response after receiving Durvalumab monotherapy in the previous study.

Figure No.04: percentage of patients who major pathological response after receiving combinatorial therapy.

All are early-stage NSCLC patients.

No patients died after the treatment. Moreover, these complex patients need multidisciplinary care. Even though these results directly involve current clinical practice they can have an impact on future perspectives. They may be successful in targeted radiotherapy for lung cancer patients.

What is stereotactic body radiotherapy (SBRT) for lung cancer?

The SBRT is a kind of stereotactic body radiosurgery(SRT) when it applies to body tumours. When the primary tumour is larger and the SRT cannot treat it, SBRT will be helpful. In addition, when the primary tumour mixes with more normal tissues SBRT is a general solution.

The SBRT can deliver a few high doses of targeted radiation to the tumour effectively. This is also a type of targeted radiotherapy for lung cancer and other types. SBRT is a good option for local control of tumours. When compared to surgical resection for tumours less than 3cm. However, due to the ability to create complications, use of SBRT is only used for peripheral lesions.

Stereotactic body radiotherapy is useful for cancer outpatients.

How about the involvement of 177Lu-labeled cyclic RGD peptide in imaging and targeted radiotherapy for lung cancer?

This is for the subtype Non-Small Cell Lung Cancer (NSCLC) as imaging and targeted radionuclide. These are still preclinical studies.

The αvβ3 integrin receptor subtype is a biomarker in lung cancer.it is responsible for the growth and progression of lung cancer. The extracellular domain of the receptor has a binding site for RGD based sequences. Therefore it will be an excellent target for imaging and treatments. Uniquely targeting αvβ3 integrin receptors by short peptides will be successful.

In the research published in BioOrganic Chemistry in July 2020 radiolabeling of DOTA-E(cRGDfK)2 with 177Lu was used. The results were positive to clarify there was a 95% radiopeptide binding to the specific receptor.

In summary, radiopeptide will be a promising agent for imaging and targeted radiotherapy for lung cancer.

What are the Current obstacles and how will be the future of targeted radiotherapy for lung cancer?

Delivering the drug to the correct target is an essential part of the targeted radiotherapy for lung cancer. If the delivery of the radionuclide is not accurate, there will be no effect.

The drug should deliver to the site of action with the required dose to produce the desired effect.

Normally available drug delivery systems for instance oral or injectables will no longer be effective in this approach. Hence a new developed effective delivering strategy should come up. Recent innovations in biomedical sciences, drug delivery systems using nanoparticles, advanced polymer chemistry showed several new pathways. Furthermore targeted radiotherapy for lung cancer using gene therapy needs safe drug delivery to the correct site. Otherwise, they can harm nearby tissues as well.

 

 

 

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