Tumors of the choroid plexus epithelium are rare and account for only 0.5% of all tumors in adults and children. The tumors occur mostly in infants, but have been reported in adults, too. Metastases are mostly within the central nervous system. On histology, the WHO classification 2007 recognizes choroid plexus papilloma (CPP) as the relatively benign (Grade I), and choroid plexus carcinoma (CPC) as the malignant version (Grade III) and atypical choroid plexus papilloma (APP) as an intermediate form (grade II). Tumors have been described, which progressed from lower to higher grade lesions and even the lowest grade can present as metastatic disease. P53 and SV40 can play a role in the molecular genesis of these tumors, in clinical and experimental tumors, PDGF-receptors in the growth of established tumors. The treatment of choroid plexus tumors should start with maximal reasonable achievable tumor resection of all sites. Radiation improves the prognosis, but most children are critically young for radiation. The CPT-SIOP-2000 study has established these tumors to be chemotherapy responsive to combinations of etoposide, vincristine and either carboplatin or cyclophosphamide, but which agent was superior could not be determined. It will remain open until all hospitals have opened the following study CPT-SIOP-2009. The new study is more detailed and more complicated. It starts with four treatments arms. Furthermore, patients not treated according to the studies can still be registered in the registry, since there is some information to be learned even when the treatment differs. All those studies run through hospitals and doctors. Physicians, nurses or data-managers enter the data. However there is one way how patients and parents can donate information: through this website, the family-registration. All these sources of information are brought together by the international study group to learn the most possible about the disease.
The CPT-SIOP-2000 study
In 2000 a study was launched with the aim to gain information concerning the specific role of single treatment agents, upon which further studies could be build. The available evidence suggested benefit of surgery for all patients and irradiation for patients over 3 years of age. Among the chemotherapeutic agents the best evidence was found for VP16, followed by vincristine, cyclophosphamide, and the platinum drugs. Among many interesting treatment questions, only one variable could be compared in the small number of patients available. An international discussion around this study, which occurred from 1998-2000 in various national and international groups, showed that the comparison of cyclophosphamide with carboplatin was the best feasible question. Carboplatin was preferred over cisplatin because of the lower ototoxicity and the difficulties in testing hearing in infants. Multiagent treatment was viewed as standard care in many centers. Therefore the most frequently used drugs, VP16 and vincristine, were added to both arms of the protocol. This combination of DNA-binding drugs, with topoisomerase inhibitors and mitosis inhibitors was well based on theoretical/preclinical thinking and was generally used in almost all pediatric brain tumor protocols. The majority of patients were young and the most physicians agreed that they should not receive irradiation. Therefore, radiotherapy could not be a randomized study objective internationally. For patients over three years of age, the CPT-SIOP-2000 study includes irradiation, based upon the literature review conducted for this study (J. E. Wolff et al., 1999).
The CPT-SIOP-2000 study was the first international study for children and adults with tumors of the choroid plexus and is still open for recruitment. Therefore only an interim analysis can be presented here.
Treatment Protocol
After maximal possible resection, all patients with CPC, metastasized tumors and incompletely resected atypical plexus papilloma were randomized to a treatment with either carboplatin or cyclophosphamide given together with etoposide and vincristine. After the first interim analysis at the committee meeting in Vancouver 2005, it was decided to stratify the randomization by age to keep an even number of radiated patients in each treatment group. A total of 6 courses of chemotherapy (VP16 100 mg/m2 d1-5, vincristine 1.5 mg/m2 d1 and either carboplatin 350 mg/m2 d1+2 or cyclophosphamide 1000 mg/m2 d1+2), and additional irradiation after the second course for those who are older than 3 years of age was given. Patients with metastasized APP and CPC, and patients with non-metastasized CPC non-responsive to chemotherapy (SD, PD) received craniospinal irradiation with 35 Gy and local boost up to a total of 54 Gy. Patients with choroid plexus papilloma and completely resected atypical papilloma were closely followed without further treatment.
The CPT-SIOP-2009 study
The CPT-SIOP-2009 Study will address the question, which of four different chemotherapy protocols is superior. The protocols are: a) standard: cyclophosphamide, carboplatin, vincristine, etoposide, b.) doxorubicin, actinomycin D, Cisplatin, c) high dose methotrexate and d.) temozolomide, irinotecan. In addition, radiation and intrathecal cytarabine is given to all treatment arms following a risk adapted algorithm uniform in all treatment arms. Concerning the statistical method, the study design uses a Bayesian weed out.
Inclusion criteria include all histological proven choroid plexus tumor all of which can be enrolled in the registration.
Exclusion criteria only apply to the treatment protocol and the randomization and include choroid plexus papilloma without metastases and without documentation of growth, completely resected atypical choroid plexus papilloma, previous radiation or chemotherapy, and the typical contraindications for chemotherapy.
Details of the additional treatment are:
a) Standard arm: Alternating chemotherapy cycles with VP16 100 mg/m2 over 1 hour on days 1-5, carboplatin 350 mg/m2 over 2 hours on day 2 and 3, vincristine 1.5 mg/m2 on day 5 alternating with: VP16 100 mg/m2 over 1 hour on days 1-5, cyclophosphamide 1 g/m2 over 1 hour on day 2 and 3, vincristine 1.5 mg/m2 on day 5. Six blocks are given in 4 week intervals (day1 to day1). Radiation is given between the second and the third cycle only to a small subgroup of patients defined by age histology staging and response to the first to cycles of chemotherapy.
b) Doxorubicin/cisplatin arm: Doxorubicin 25 mg/m²/day over 12 hrs on days 1-3, Dactinomycin 45 µg/kg/day (max. 2 mg), i.v. on day 1, and Cisplatin 70 mg/m²/d over 6 hrs on day 4, and Vincristine 1.5 mg/m²/day (max. 2 mg), i.v. on days 8, 15. An identical second cycle is started on day 28 if the side effects allow it. The further treatment is identical to the standard arm with four more cycles of chemotherapy following radiation in some of the patients in all treatment arms.
c) Methotrexate arm: 5g/m2 over 24 hours with leucovorin rescue at hour 42 given tree times on days 1 15 and 29. The further treatment is identical in all four treatment arms.
d) Temozolomide Irinotecan arm: Temozolomide is given at 150 mg/m2/day x 5 days orally and combined with irinotecan 50 mg/m2/day x 5 days as one hour infusions. Two of these cycles are followed by the common radiation – four cycle chemotherapy protocol.
Irradiation: The majority of patients will not receive irradiation. A few subgroups of patients will receive radiation after the second cycle of chemotherapy. The indication for radiation, the field and the dose will be specified based upon the patient’s age, tumor histology, staging and response to the two first cycles of chemotherapy. Maximal radiation will be given to patients over 3 years of age with metastatic CPC non responsive to the first two cycles. These patients receive craniospinal irradiation with 35 Gy and local boost up to a total of 54 Gy.
The CPT-SIOP-Registry
The CPT-SIOP-Registry Is built in the treatment studies, but can also be used alone. It allows hospitals and physicians to provide information form their choroid plexus patients to be used in research. This is useful if the treatmetn studies can not be opened in teh hospital, or if other treatments have been given. The data will be analysed to descibe the frequency of the tumors in all their subtypes. If there are unsusal treatment successes, they will be analysed and brought forward to the group for consideration for the next protocol. Also the data can serve as control groups for the structured prospective treatment protocols.
The CPT-SIOP-Rez-Study
The CPT-SIOP-Rez-Study When the first treatment did not work, and the tumor came back, a second line treatment is recommended. For some patients the drug temozolomide might help. Dr Tezer Kutluk from Ankara, wrote this protocol and collects the data.