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Is proton craniospinal irradiation better than involved-field radiation therapy for leptomeningeal?

Radiation therapy is part of therapeutics to manage leptomeningeal disease. It destroys the tumor cells disseminated in the cerebrospinal fluid. Involved-field radiation therapy is the standard-of-care radiotherapy modality in leptomeningeal disease but it does not provide long-term benefits. Recent improvements in radiation therapy have provided other options for the management of leptomeningeal disease. One such emerging modality is proton craniospinal irradiation. This blog compares the safety and efficacy of these two modalities to figure out the better treatment modality for the patients.

Let’s recall some basics of leptomeningeal disease

Leptomeningeal disease is a late complication of various types of cancer in which cancerous cells are accumulated in the leptomeningeal compartment of the central nervous system. It is a rare but very serious condition that can result when certain types of cancer, such as lung cancer, breast cancer, and melanoma, reach advanced stages. Leptomeningeal disease has a poor prognosis and the survival time is often as low as a few months.

Leptomeningeal disease

The symptoms arise when the tumor mass causes dysfunction of the nerves or disrupts the natural flow of cerebrospinal fluid, thus increasing the intracranial pressure in the head (a condition called hydrocephalus). These symptoms can range from headache and lethargy to loss of sensations, blurred vision, and difficulties in swallowing, talking, and maintaining balance. The diagnosis is based on neuroimaging modalities such as magnetic resonance imaging and computed tomography as well as the evaluation of the cerebrospinal fluid.

How is leptomeningeal disease being managed?

Due to the poor prognosis of leptomeningeal disease, the management is mainly based on providing palliative care. This includes the use of medications such as steroids, antidepressants, and anticonvulsant drugs to relieve pain, depression, and seizures respectively [1]. Furthermore, ventriculoperitoneal (VP) shunt is installed to relieve hydrocephalus.

However, in some low-risk patients, aggressive interventions such as radiation therapy and chemotherapy can prolong survival. Radiation therapy in leptomeningeal disease can be of several types:

  • Focal radiation

  • Whole brain radiation

  • Craniospinal irradiation

Involved-field radiotherapy versus proton craniospinal irradiation

As mentioned above, there are several options for radiation therapies in leptomeningeal disease. Of these, involved-field radiation therapy is the standard of care. In this procedure, beams of radiation are targeted at tumor masses in the leptomeninges. The destruction of these masses provides local relief and lowers the abnormally raised pressure of the cerebrospinal fluid [2]. But the actions of involved field radiation therapy are not durable. Craniospinal irradiation, in contrast, delivers radiation to the cerebrospinal fluid throughout the central nervous system and is better suited to control the overall disease progression. But it causes some toxicities, such as myelosuppression (a reduced activity of bone marrow that results in a decrease in the number of blood cells) and enteritis (inflammation of the small intestine) in adults who have already received radiation therapy [3]. However, the use of proton beams in this modality has improved its safety profile.

Clinical evidence of proton craniospinal irradiation’s superiority

A phase 2 clinical trial comparing these two forms of radiation therapies in leptomeningeal disease has been completed recently. In this trial, 42 patients received craniospinal irradiation whereas 21 received involved-field radiotherapy. According to the reported results:

  • The median progression-free survival of the patients receiving craniospinal irradiation was 5.2 months greater than the group which received involved-field radiotherapy [4].

  • In terms of overall survival, craniospinal irradiation had a benefit of 3 months over the involved-field radiotherapy [4].

  • The safety of both these two interventions was similar [4].

In a nutshell

Craniospinal irradiation has emerged as a potential alternative to field-involved radiotherapy in cases where prolongation of survival is concerned. It is proven to be more efficacious and at least as safe as involved-field radiotherapy. The currently available clinical evidence is leaning towards craniospinal irradiation but multiple phase 3 clinical trials with larger sample sizes are required to help make this decision. Despite this, it is important to keep in mind that the management of leptomeningeal disease follows a highly individualized approach based on the type of primary cancer and the phenotype of the disease. Therefore, having another option of radiotherapy helps provide the best-suited treatment to a patient.


  1. E. Le Rhun and M. Weller, “Treatment of Leptomeningeal Metastases,” in Central Nervous System Metastases, M. Ahluwalia, P. Metellus, and R. Soffietti, Eds. Cham: Springer International Publishing, 2020, pp. 301–311. DOI: 10.1007/978-3-030-23417-1_24.

  2. J. P. Thakkar, P. Kumthekar, K. S. Dixit, R. Stupp, and R. V. Lukas, “Leptomeningeal metastasis from solid tumors,” J Neurol Sci, vol. 411, p. 116706, Apr. 2020, DOI: 10.1016/j.jns.2020.116706.

  3. S. Taillibert and M. C. Chamberlain, “Leptomeningeal metastasis,” Handb Clin Neurol, vol. 149, pp. 169–204, 2018, DOI: 10.1016/B978-0-12-811161-1.00013-X.

  4. J. T. Yang et al., “Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis,” J Clin Oncol, vol. 40, no. 33, pp. 3858–3867, Nov. 2022, doi: 10.1200/JCO.22.01148.



IIT Guwahati
University of Manchester
Rhenix Lifesciences
American university of Sharjah
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