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Paper Abstract

Is craniospinal irradiation safe for patients with leptomeningeal disease?

Craniospinal irradiation is an effective way of killing cancer cells in the cerebrospinal fluid. But the conventional craniospinal irradiation technique, consisting of high-energy photons (x-rays), causes various toxicities that adversely affect the quality of life of the patients. Proton-based craniospinal irradiation has emerged as an alternative to the conventional technique with fewer adverse effects. This blog considers the clinical evidence of the safety and efficacy of proton craniospinal irradiation to answer whether it is a good option for leptomeningeal disease patients or not.

What is leptomeningeal disease?

Leptomeningeal disease is a fatal complication that results when the tumor cells spread into the space between the leptomeninges. It can result from a variety of cancer types but most patients have lung cancer, breast cancer, or melanoma as their primary disease.

 

The brain and the spinal cord are protected by three layers of meninges with a fluid flowing between them, called the cerebrospinal fluid. The middle and innermost layers and the space between them are referred to as the leptomeningeal compartment. At an advanced stage of cancer, the cancer cells metastasize (move away from the primary site and reach secondary sites by proliferation) and may settle between the leptomeninges.

 

As a result, the patients develop symptoms of increased intracranial pressure and nerve dysfunction. It is diagnosed by various neuroimaging studies of the central nervous system (brain and spine) and laboratory analysis of cerebrospinal fluid drawn through a lumbar puncture (spinal tap). The treatment involves palliative care, chemotherapy, and radiation therapy.

Leptomeningeal disease.jpg

Radiation therapy in leptomeningeal disease

Radiation therapy is an essential part of the aggressive treatment of leptomeningeal disease which aims to destroy the tumor masses in the leptomeninges and eradicate cancerous cells from the cerebrospinal fluid. There are 2 general types of radiation therapy being employed in the management of the leptomeningeal disease.

 

  1. Involved-field radiotherapy: The standard of care treatment in adults is involved-field radiotherapy which provides local relief against the symptoms by destroying the masses of tumor cells that clog up the flow of cerebrospinal fluid and/or cause nerve dysfunction.

  2. Craniospinal irradiation: It targets the entire central nervous system with a relatively low dose of radiation and is, therefore, better suited to kill the tumor cells disseminated in the cerebrospinal fluid. In other diseases, such as medulloblastoma, craniospinal irradiation is given to patients who already have cancer cells in their meninges or are at risk of developing this complication [1].

Drawbacks of conventional craniospinal irradiation

In this procedure, high-energy photons are delivered to the entire central nervous system by merging multiple beams. Radiation destroys the clumps of tumor cells in the bulky disease but the damage caused by direct exposure of healthy tissues as well as the exit dose from the spinal fields leads to several short- and long-term toxicities [2].

 

The short-term adverse effects are:

  • Fatigue

  • Headache

  • Nausea

  • Vomiting

  • Dry skin

 

Whereas, the long-term side effects are:

  • Retardation of spine growth

  • Hormonal imbalances

  • Risk of secondary cancers

 

These adverse effects severely impact the quality of life of the patients and therefore alternate ways of providing therapeutic radiation to the central nervous system without causing undesirable long-term effects are being investigated.

What is proton radiation?

Proton beam craniospinal irradiation is an extension of conventional craniospinal irradiation therapy which uses protons beams instead of photons to destroy the tumor cells. Protons are first accelerated to very high velocities in a particle accelerator which allows them to penetrate the normal tissue and reach the tumor. Once in the tumor, the positively charged protons attract the negatively charged DNA of cancer cells and destroy them.

 

Proton beams do not produce exit doses and thus, have limited adverse effects. Another advantage of proton beams is that they are more precise as compared to x-rays [3]. Proton beam therapy has been around for a few decades but its clinical use is becoming more widespread only recently.

Proton beam craniospinal irradiation is safe and effective in leptomeningeal disease!

A clinical trial to assess the safety and efficacy of proton craniospinal irradiation recruited 24 patients and treated them with proton craniospinal irradiation consisting of 30 Gy in 10 fractions [4]. Most patients had non-small-cell lung cancer as their primary malignancy. The median age of these patients was 52 and their median score on the Karnofsky performance scale was 70. According to the reported results:

  • Only 2 patients experienced dose-limiting treatment-related toxicities. One of these patients developed grade 4 lymphopenia (deficiency of white blood cells) while the other had grade 4 lymphopenia, grade 4 thrombocytopenia (deficiency of platelets), and grade 3 fatigue.

  • In both patients, these adverse effects were resolved without treatment.

  • Other patients experienced similar toxicities but with a lower grade that did not limit the dose of radiotherapy.

  • In addition, the patients reported weakness, changes in the pattern of bowel movement, and worse moods.

  • The median progression-free survival from leptomeningeal disease was 7 months and the median overall survival was 8 months (NCT03520504).

To conclude

Leptomeningeal disease patients have a compromised bone marrow reserve due to extensive treatment as part of their primary tumor care which makes them prone to treatment-related toxicities. According to the current clinical evidence, proton craniospinal irradiation provides a safe option for controlling disease progression in such patients. Multiple clinical trials with larger sample sizes and a broader primary tumor population are required to further confirm the safety and evaluate, in detail, the efficacy of proton craniospinal irradiation in leptomeningeal disease.

References

  1. Ho, E.S.Q. et al. 'A review of dosimetric and toxicity modeling of proton versus photon craniospinal irradiation for pediatrics medulloblastoma'. Acta Oncol. (2017) 56(8), 1031–1042. DOI: 10.1080/0284186X.2017.1324207.

  2. Mahajan, A. 'Proton Craniospinal Radiation Therapy: Rationale and Clinical Evidence. International Journal of Particle Therapy. (2014) 1(2), 399–407. DOI: 10.14338/IJPT.14.00005.1.

  3. 'What Is Proton Beam Therapy for Cancer?' [https://www.verywellhealth.com/proton-beam-therapy-actions-uses-side-effects-4147398]. Verywell Health.

  4. Yang, T.J. et al. 'Clinical trial of proton craniospinal irradiation for leptomeningeal metastases'. Neuro Oncol. (2020) 23(1), 134–143. DOI: 10.1093/neuonc/noaa152.

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