Dr. Paulino provides a concise yet complete review of the radiotherapeutic management of patients with medulloblastoma. Radiotherapy treatment planning for medulloblastoma is complex, requires considerable attention to detail, and remains the subject of debate and clinical research. Clearly, this is an area of neuro-oncology in which multidisciplinary research has played a significant role in improving survival for children and young adults with this disease.
Ironically, perhaps, research on the radiotherapeutic management of medulloblastoma has resulted in a shift from less treatment (treatment of the tumor volume only prior to 1950s), to more treatment (treatment of the neuraxis), to attempts to treat less again (reduction in dose to the neuraxis, deferral of radiation with the use of chemotherapy). Even in terms of chemotherapy, there is now a strong bias among many investigators to use adjuvant chemotherapy in all stages of medulloblastoma, whereas in the past its use was restricted to poor-risk patients. Indeed, the definition of "risk" has undergone significant change over the last decade, depending less on Chang stage classification for local tumor burden and more on the extent of postoperative residual disease as measured by MRI.
All of these changes have come about because of careful observation and analysis of clinical outcomes, primarily because of clinical research from the pediatric cooperative groups in the United States and Europe. Two areas of research are particularly important, and in many ways linked: (1) attempts to reduce toxicity by lowering the craniospinal dose of radiation and (2) efforts to improve progression-free survival in low-risk patients by adding adjuvant chemotherapy.
Attempts to Reduce Radiation Dose
Dr. Paulino thoroughly discusses the attempts that have been made to reduce radiation dose to the brain and spine by minimizing actual total dose delivered or altering the fractionation scheme to potentially reduce late toxicity, as well as by the addition of chemotherapy. These approaches have had mixed results.
Various reports from single institutions using lower-dose craniospinal radiotherapy (< 30 Gy) have been published.[1,2] Single-fraction dose schedules have been used most frequently, often reducing the spinal dose to 24 Gy. In patients with good risk factors, progression-free and overall survival rates appear to be comparable to those seen historically using higher-dose treatment (36 Gy). These studies have had sufficient heterogeneity with regard to patient populations and actual treatment used, however. Thus, the results could have been biased due to patient selection factors.
A phase III study, CCG 923/POG 8631, eventually was initiated in patients with low-risk features. This study randomized patients to standard-dose or lower-dose radiation. Initial results seemed to suggest that the lower-dose radiation arm would result in higher rates of exoprimary failure, and the study was suspended prior to full accrual. A more recent analysis of this study cast doubt on that observation, and it is possible that the study question in this now closed trial will not be answered as a consequence.
A second intergroup study, CCG 9014/POG 9331, randomized patients with good-risk features to standard-dose radiation or lower-dose craniospinal radiation with adjuvant chemotherapy. Unfortunately, this study also closed early, this time because of insufficient accrual, suggesting a significant bias toward these approaches among investigators as well as patients. Thus, the question of whether one can lower the dose of craniospinal radiotherapy has still not been answered.
Additional attempts to reduce craniospinal dose have included the use of hyperfractionation techniques and the addition of chemotherapy to radiation in lower-risk groups similar to the patients in the CCG 9014/POG 9331 study. For the most part, these trials have been uncontrolled.
Our group and others began to use hyperfractionation schedules with the hope of safely increasing dose to the local tumor while decreasing dose to the brain and spine. Lower doses per fraction were used in an attempt to minimize late effects in nonproliferative neural tissue, and more frequent dosing was employed to potentiate cytotoxic effects in acute-reacting tissue, such as tumor. We learned early on that such an approach was inadequate in terms of preventing exoprimary relapse when 24 Gy was given to the spine and brain in patients without obvious disease in those areas. Clearly, 24 Gy was "biologically" inappropriate to control tumor in areas of the brain and spine at risk of relapse. However, in selected patients, the delivery of 72 Gy to the primary tumor site in the posterior fossa was found to be effective in controlling local disease, clinically tolerable, and without the long-term risk of radiation necrosis.
In CCG 9931, higher doses to the spine and brain are now being tested following intensive preradiation chemotherapy in patients with high-risk features. It may be possible to improve local tumor control rates, a significant clinical problem, by increasing dose to the primary and metastatic tumor sites through the use of hyperfractionation techniques. Many questions still remain about this approach, including the most basic ones, such as efficacy relative to standard single-fractionation schemes, appropriate dose, and late effects. Thus, hyperfractionation must still be considered investigational.
The use of adjuvant chemotherapy has traditionally been reserved for patients with high-risk features, such as those with residual disease following surgery or tumor spread beyond the primary site. Recent reports strongly suggest that, in some high-risk patients, the addition of chemotherapy may result in equal or better 5-year progression-free survival rates than those observed in patients with low-risk factors who are treated with radiation alone. These reports, most notably those using the combination of lomustine(Drug information on lomustine) (CeeNu), cisplatin(Drug information on cisplatin) (Platinol), and vincristine following radiation, are compelling, and have resulted in a new study being conducted by the CCG and POG (protocol A9961). This study will randomize patients with low-risk features to one of two chemotherapy regimens following craniospinal radiation (2,340 cGy to the brain and spine and 5,580 cGy to the primary tumor site). This study is being conducted despite a number of previous controlled phase III studies showing no survival benefit from the addition of chemotherapy to radiation in low-stage patients.[6,7]
A Different Chemotherapy Regimen
The chemotherapy that will be used in the new study differs from the regimens used in these older studies. In the new study, cisplatin will be added to lomustine and vincristine and will be compared to cyclophosphamide(Drug information on cyclophosphamide), cisplatin, and vincristine. The hope is that either of these chemotherapy regimens not only will "substitute" for the reduced craniospinal radiation dose, lessening the risk of exoprimary relapse, but also will result in higher progression-free survival rates than have been seen previously with standard-dose radiation alone. All of these results need to be accompanied with less neurocognitive, endocrine, and spinal toxicity than has been seen with higher-dose radiation. If this study accrues a sufficient number of patients to keep it open for full enrollment, the answers to the study questions may be only a few years in coming. Thus, in 1997, low-risk patients enrolled in this study will all receive chemotherapy.
It is also important to keep in mind that although 5-year progression-free survival rates of patients with medulloblastoma appear to be improving, 10-year results are important as well. This is true in terms of actual progression-free survival, as well as overall "quality" survival and the potential risk of second malignancies in these children with low-risk features who are treated with both radiation and alklyator-based chemotherapy.
The possibility of curing medulloblastoma does exist, particularly in patients with low-risk features. Dr. Paulino's review is important and timely, and should encourage physicians who treat these patients to continue to ask questions and to participate in clinical trials that attempt to answer them.