Risk-benefit analysis of a combination of topo-isomerase modulators Irinotecan and Etoposide in Refractory Metastatic Breast Cancer showed modest efficacy, but the toxicity of this regimen was very high and experienced by over 70% of patients. Risks outweigh benefits for this combination in patients with metastatic breast cancer.
Metastatic Breast Cancer is the very advanced, stage IV cancer that has spread to other regions of the body (most often the bones, lungs, liver or brain). There are only 6% of women who are diagnosed with metastatic breast cancer at first diagnosis. Most other cases of invasive or metastatic breast cancer is when the cancer has relapsed in the patient after completing prior treatment and being in remission for many years. Metastatic breast cancer, mostly prevalent in women but also found in a small percentage of men, has a very poor prognosis with a 5-year survival being less than 30% as per data from the American Cancer Society Publication (Cancer Facts and Figures, 2019).
Metastatic breast cancer is treated with many different therapy regimens including different classes of chemotherapy, immunotherapy, targeted therapy, hormonal therapy and radiation therapy options, through a trial and error process, since there is no defined treatment for this cancer. Treatment choice is dependent on the molecular characteristics of the prior breast cancer cells, past breast cancer treatments, clinical status of the patient and where the cancer has spread. Towards finding a more optimal and effective treatment option for metastatic breast cancer, a clinical trial done at the University of Arizona Cancer Center, evaluated the combination of two drugs – Irinotecan (Camptosar) and Etoposide (VePesid), in a group of women with refractory metastatic breast cancer (Segar JM et al., The Oncologist, 2019).
The clinical trial details, scientific rationale of the study and results are as follows:
Details of Clinical Trial (NCT00693719) which evaluated Irinotecan & Etoposide in Metastatic Breast Cancer
- There were 31 women enrolled in this single arm, phase II clinical trial, between ages of 36-84 years.
- 64% of these women had the hormone positive and HER2 negative type of breast cancer.
- The women had been treated with a median of at least 5 prior therapies and were already resistant to prior anthracycline, taxane and capecitabine therapy.
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Scientific Rationale for the Study
- The reasoning behind the trial was to try a new set of chemotherapy drugs that had both shown documented activity in breast cancer patients and the combination was validated preclinically.
- Both Irinotecan and Etoposide are natural, plant-derived compounds that are modulators of topoisomerase (TOP) enzyme isoforms. TOP enzymes are required for DNA replication and transcription, both critical processes for a rapidly growing cancer cell. Interfering with TOP action causes DNA strand breaks, DNA damage and induces cell death.
- Irinotecan is a TOP1 and Etoposide a TOP2 modulator. Reason for combining both TOP1 and TOP2 inhibitors is to address the compensatory activation of the other isoform when one of the isoforms is suppressed.
Clinical Trial Results
- There were 24 patients that could be evaluated for efficacy of this combination regimen of Irinotecan and Etoposide. 17% had a partial response and 38% had stable disease.
- All 31 patients were evaluated for toxicity and 22 of the 31 (71%) experienced treatment related grade 3 and 4 adverse events. Most common toxicity was neutropenia, which is the presence of abnormally low levels of neutrophils in blood that could increase susceptibility to infections.
- Study was terminated early since toxicity burden was severe and outweighed the efficacy of the combination.
Metastatic breast cancer tumors are difficult to treat. Although combination chemotherapy has some benefit in controlling the cancer, it cannot be used extensively and long term due to its severe toxicity profile and quality of life impact on the patient. Evaluating the mutation profile of the metastatic tumor could help identify combinations of more targeted therapy approaches with lower side-effects. The risk of using the specific combination of topoisomerase inhibitors Irinotecan and Etoposide outweighed the benefits and therefore may not be used in treating metastatic breast cancer.
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