Local Chemotherapy More Effective Than Systemic Chemotherapy in Glioblastoma

When combined with immunotherapy, delivering chemotherapy drugs directly to the brain may be more effective than systemic chemotherapy in the treatment of glioblastoma.

Glioblastoma is an aggressive form of brain cancer, with an average survival time of a little over 1 year after diagnosis. Current treatments include chemotherapy, radiation, and the surgical removal of the tumor.

Due to the aggressive nature of the disease, there is a great need for newer, more effective immunotherapies. However, the current standard treatment strategy poses a challenge due to the potential toxic effects of systemic therapies that can damage or interfere with the immune system, subsequently weakening the success of the immunotherapy treatment that follows.

In a study published in Science Translational Medicine, investigators used glioblastoma mouse models to determine whether one method of chemotherapy delivery was better than the other.

The investigators administered 200 milligrams per kilogram of the immunotherapy drug, anti-PD-1, in a group of mice with glioblastoma. Over a 2-week period, the mice were treated with chemotherapy systemically or directly to the brain.

The mice were divided into 2 groups of 15. In the systemic chemotherapy arm, the investigators injected 30 milligrams per kilogram of carmustine into the bellies of the mouse models, 3 times a week. In the local chemotherapy arm, a wafer covered in molecules that bound carmustine was directly implanted into mice with established brain tumors, allowing sustained release of the drug over 1 week, according to the study.

When the chemotherapy treatments ended, the investigators took blood samples from the brain, bone marrow, blood, and lymph nodes of the mouse models. Samples were taken again at nearly 2 weeks post-chemotherapy and at the 4 month mark.

To measure immune system integrity, the investigators focused on counting the number of lymphocytes.

The results of the study showed mice in the systemic chemotherapy arm had lower levels of lymphocytes than mice in the local, long-lasting chemotherapy arm. Two weeks after treatment, the mice administered systemic chemotherapy only had about one-third of lymphocytes in the blood compared with mice given the local chemotherapy.

The findings suggest that the depletion of lymphocytes caused by systemic chemotherapy is likely counterproductive to producing an effective anti-tumor immune response, according to the authors.

During a second experiment, the investigators sought to determine whether the local versus systemic chemotherapy in conjunction with immunotherapy affected survival in mice with glioblastoma.

The results of the study showed that when the mice were given chemotherapy locally, it acted together with the immunotherapy drug to increase survival to approximately 80% after 100 days, compared with mice who received immunotherapy alone, local chemotherapy alone, or combined systemic chemotherapy and immunotherapy, which had a survival rate of approximately 50% after 100 days.

To assess the immune system’s memory, the investigators administered local chemotherapy or systemic chemotherapy in conjunction with immunotherapy to the mice, and then implanted them with more tumors. They found that the mice with the systemic chemotherapy and immunotherapy all died when injected with more tumors, while the mice with local chemotherapy and immunotherapy survived.

The authors said that these findings suggest the systemic chemotherapy greatly weakens the immune system. Furthermore, the weakening of the immune system is not specific to carmustine, but occurs in several types of systemic chemotherapy.

Additionally, the investigators were able to reverse the treatment protocols and give the chemotherapy before the immunotherapy to determine whether it worked better and improved survival. However, there was no observed difference in survival time.

“We understand that our research was done in a mouse model and not in humans, but our evidence is strong that systemic chemotherapy alters the immune system in a way that it never fully recovers,” said investigator Michael Lim, MD. “With aggressive cancers like glioblastoma, it is important that we don’t handicap the defenses we may need to add alternative treatments, such as immunotherapy, to chemotherapy.”