By Tanya Tekautz, MD; Michal Bahar, MD; and Johannes Wolff, MD
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The rare, highly invasive pediatric brain tumors known as choroid plexus carcinomas (CPCs; Figure 1) are often associated with Li-Fraumeni syndrome (LFS). This hereditary disorder, usually characterized by an underlying germline mutation of the TP53 tumor suppressor gene, predisposes carriers to sarcomas and malignancies of the brain, breast and adrenal glands.
CPC cases, which primarily involve infants and children younger than 2 years of age, account for less than 5 percent of all brain tumors. Their scarcity has precluded randomized trials, requiring that treatment guidance for patients with CPC be derived from a limited record of case studies, small series reports and expert opinion.
Figure 1. T1-weighted MRI with contrast showing a choroid plexus carcinoma.
Surgical resection of the tumor to the maximal extent possible is generally considered preferred initial treatment, followed by adjuvant therapy, although the role and benefits of chemotherapy and radiation therapy are not well-defined. Radiation therapy improves survival in many patients with high-grade embryonal brain tumors and is often recommended for patients with CPC. However, the significant, irreversible and progressive neurocognitive deficits and growth impairment that radiation causes, especially in very young children, make its use controversial.
Previous research has demonstrated the crucial role of TP53 in cell cycle control, genomic stability and response to DNA damage, such as from ionizing radiation. Mutation of TP53, as occurs in LFS, not only abrogates the P53 protein’s normal tumor suppressive function but also may disrupt cellular regulatory networks, thus enabling tumor cells to avoid genotoxic signals such as from gamma radiation, circumventing senescence and programmed cell death.
In light of that research, we hypothesized that LFS patients who harbor the TP53 mutation will have primary radioresistance, with resulting implications for treatment and survival.
Supportive evidence comes from research by Boyle and colleagues demonstrating that eight TP53 mutation-carrying fibroblast strains from seven LFS donors showed increased cellular resistance to ionizing radiation, although at varying levels. Also, Tabori and colleagues reported a 22 percent five-year overall survival rate among nine CPC patients with LFS and TP53 germline mutations, compared with 100 percent five-year overall survival for 11 non-LFS CPC patients with TP53 wild-type tumors — a difference presumably due to heightened chemo- and radiation therapy resistance in the TP53-mutant strains.
We conducted a literature analysis to test our supposition that radiation therapy should be avoided in CPC patients with LFS, using a database of 11 research articles chronicling the treatment outcomes of 28 CPC patients with LFS. We compared overall survival among patients treated with radiation therapy, chemotherapy or surgery alone. The results of our meta-analysis were recently published in Anticancer Research.
Among the 28-patient cohort, 24 patients had germline TP53 mutations, two had phenotypic characteristics of LFS (one without TP53 mutation, the other untested), and two had positive p53 staining but no TP53 mutations. Median age at diagnosis was 12 months. All patients underwent surgical resection, with gross total resection of the primary tumor achieved in 15 cases, partial resection in one case and unknown results in 10 cases.
Twenty-seven patients received chemotherapy treatment at diagnosis, using a variety of regimens.
Eleven patients received radiation therapy, including five who were treated after tumor recurrence. Of those 11, six died from disease recurrence or progression and three from secondary malignancies. Two radiation recipients were alive and disease-free at the study’s completion.
Seventeen patients did not receive radiation therapy. One of those developed a secondary malignancy, seven died of cancer progression and nine remained alive at the study’s completion.
Analysis showed a marginally significant (P = .056) two-year overall survival advantage for patients who did not receive radiation compared with those who did (0.58 ± 0.12 percent vs. 0.18 ± 0.1 percent, respectively).
It is possible that cancer deaths among patients who underwent deferred radiation therapy may actually reflect instances where radioresistance developed at relapse, rather than representing primary radiation therapy failure. Therefore, we reanalyzed our data by excluding the five patients who received treatment at recurrence.
Our results continued to show a survival advantage for the patients not undergoing radiation therapy, although at a level that did not reach statistical significance (P = .3), likely due to the small sample size.
The heightened rate of tumor progression or relapse after radiation therapy apparent from our analysis is worrisome. The above-cited research by Boyle and colleagues suggests a mechanism of action: Doses of gamma radiation below the level required for universal cellular lethality may induce selective survival of tumor cells with additional genetic aberrations, accelerating tumor growth potential. Also, cells from LFS patients with or without TP53 mutation have been shown to have a reduced capacity to repair or eliminate chromosomal damage of the sort caused by ionizing radiation, which may contribute to these patients’ cancer predisposition.
Admittedly, a retrospective literature review such as ours has limitations imposed by the publication bias of the case reports and series upon which it is based. However, a prospective randomized clinical study also would have inherent reliability limits due to the rarity of CPC cases and the resultant small sample size. Our meta-analysis provides the best possible evidence to date regarding radiation therapy outcomes in CPC patients with LFS.
In light of the foregoing considerations, we propose that radiation therapy should be avoided in all LFS patients with CPC (i.e., those with TP53 mutations). These patients should be classified separately and treated with radiation-sparing protocols.
At a meeting organized by Cleveland Clinic Children’s in conjunction with the 2014 International Society of Paediatric Oncology Annual Congress in Toronto, an international group of pediatric oncologists concurred with this proposal, deciding to no longer recommend radiation as first-line treatment for CPC with LFS. Testing for TP53 mutations and assessing family histories are vital in the management of newly diagnosed CPC patients.
Dr. Tekautz is a pediatric and young adult neuro-oncologist in Cleveland Clinic Children’s Department of Pediatric Hematology, Oncology and Blood and Marrow Transplantation. Dr. Bahar is a fellow in the department, and Dr. Wolff is formerly its chairman.