Presenter: W.R. Polkington Presenter's Affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY Type of Session: Scientific
Medulloblastoma, a primary neuroendocrine tumor arising in the posterior fossa, represents the second most common pediatric central nervous system (CNS) tumor, and accounts for 20% of pediatric CNS tumor diagnoses.
Male children are about twice as likely to develop medulloblastoma as females, and median age of presentation during childhood is 7 years.
Resection is attempted in all patients, and stratification as standard- or high-risk is performed following surgical treatment. High-risk features include age less than 3 years, residual tumor of more than 1.5 cm2 following resection, presence of tumor cells in the cerebrospinal fluid, and metastatic disease within the central nervous system or beyond.
Multimodality treatment, consisting of postoperative radiotherapy and chemotherapy, is recommended for most patients. Radiotherapy is delivered to the entire craniospinal axis, and a boost delivered to the posterior fossa.
Historically, patients received 35 Gray (Gy) to the craniospinal axis followed by posterior fossa boost to 55 Gy total.
In recognition of significant toxicities and late effects caused by this treatment, efforts have been ongoing to reduce radiotherapy dose delivered. In an important study conducted by the International Society of Pediatric Oncology (SIOP), delivery of 25 Gy to the craniospinal axis was found to be equivalent to 35 Gy for patients with standard-risk disease (Bailey, Med Ped Onc, 1995). This has been confirmed in more recent randomized clinical trials (Merchant, IJROBP, 2008).
Trials investigating the possibility of further reducing this dose to 18 Gy for standard-risk patients are ongoing.
Although reduction of the craniospinal dose has led to decreased risk of many late-effects associated with treatment of medulloblastoma (including growth delay, cognitive delays, and cardiac/ pulmonary toxicity), the posterior fossa boost to 55 Gy is associated with its own side effect profile.
Dose delivery to the entire posterior fossa results in significant dose being administered to the cochlea. Particularly as most patients with medulloblastoma receive cisplatin-based chemotherapy which may be associated with ototoxicity, reducing radiation dose is important in reducing risk of severe ototoxicity.
Reducing total volume of brain irradiated is also expected to reduce neurocognitive sequelae of treatment (Merchant, IJROBP, 2006).
Efforts to reduce the posterior fossa volume irradiated through use of techniques including three-dimensional conformal radiotherapy are ongoing at several institutions.
Preliminary results of reducing boost volume to encompass only the tumor bed rather than the entire posterior fossa were published in 1999 (Merchant, Neuro-Oncol, 1999), and demonstrated no increased risk of local failure with this volume reduction. Other groups have demonstrated similar findings (Douglas, IJROBP, 2002).
In 2003, results from a cohort of children with medulloblastoma treated at Memorial Sloan Kettering Cancer Center (MSKCC) with conformal boost to the tumor bed in combination with craniospinal irradiation were published, and demonstrated significant sparing of normal structures with no impact on posterior fossa failure rate (Wolden, JCO, 2003).
Since the year 2000, patients treated at MSKCC have received tumor bed boost using intensity-modulated radiotherapy (IMRT). Clinical outcomes for these patients are reported here.
Materials and Methods
From October, 2000 through December, 2007, 34 patients with newly diagnosed medulloblastoma were treated with craniospinal radiation followed by an IMRT boost to the tumor bed.
Of these, 25 patients were considered standard-risk.
19 standard risk patients were treated with 23.4 Gy to the craniospinal axis followed by a boost to the tumor bed to 55.8 Gy.
6 standard risk patients were treated on an MSKCC protocol and received 18 Gy to the craniospinal axis followed by tumor bed boost to 54 Gy, in conjunction with a monoclonal antibody 3F8 labeled with iodine-131 and delivered intrathecally.
The 9 high-risk patients received 36 Gy to the craniospinal axis followed by tumor bed boost to 55.8 Gy.
For all patients, the gross tumor volume (GTV) consisted of the resection cavity plus any residual tumor.
The clinical target volume (CTV) was composed of the GTV plus a 1 cm expansion in all directions.
An additional 0.5 cm expansion was performed to create the planning target volume (PTV).
Concurrent vincristine was delivered to 33 of 34 patients, and all 34 patients received standard adjuvant chemotherapy.
Pure-tone audiograms were evaluated, and hearing changes were graded according to the National Cancer Institute’s Common Terminology Criteria.
Median patient age was 9 years (range 4 – 46 years).
Median follow-up was 45 months.
Progression free survival was 84% at 5 years, and overall survival 97% for the entire group. Differences in progression free and overall survival were not significant between standard- and high-risk patients.
No patient developed failure within the posterior fossa outside of the boost volume.
One patient experienced failure in the posterior fossa within the boost field, one combined posterior fossa and distant failure, and one distant failure alone.
The cochlea received a mean dose of 53% (SD +/- 17) of the prescription boost dose.
A representative case was planned using three-dimensional and two-dimensional planning techniques to the same dose volume, and cochlear dose was 75% and 100%, respectively, of the prescribed boost dose.
Pre- and post-treatment audiograms were available for 16 patients, with median follow-up of 12 months. Grade 3-4 hearing loss was developed in 13% of cases.
The authors conclude that overall survival and progression free survival rates with use of IMRT boost to the tumor bed compare favorably to historical rates.
They describe a low posterior fossa failure rate, with no posterior fossa failures outside of the radiation field.
They note that this technique decreases the mean dose to the cochlea when compared to other techniques, and results in minimal ototoxicity.
Trials in pediatric oncology have resulted in great improvements in overall cure rates for most childhood malignancies, including medulloblastoma.
Unfortunately, many of the treatments utilized result in severe late effects that may limit function of adult survivors of childhood cancer.
Systematic trials for patients undergoing medulloblastoma treatment have resulted in decreased dose delivery to the craniospinal axis for standard risk patients (Bailey, Med Ped Onc, 1995; Merchant, IJROBP, 2008). This dose reduction does not appear to impact survival, and has led to decreased risk of late effects involving the heart, lungs, reproductive organs, and spinal column.
Trials to further reduce craniospinal dose are at the forefront of current Children’s Oncology Group protocols.
The treatment techniques described here are within the same vein as dose reduction to the craniospinal axis, but instead address volume of brain tissue receiving boost dose.
Prior efforts to reduce boost volume from including the entire posterior fossa to including only the resection cavity with three-dimensional conformal radiotherapy have demonstrated no increased risk of posterior fossa failure, with considerable dose reduction to the cochlea, and reduction of the volume of normal brain irradiated (Wolden, JCO, 2003).
The study described here makes use again of radiotherapy delivered to the tumor bed; however, IMRT technique is used to further reduce dose to the cochlea.
This study demonstrates overall survival and progression free survival rates that are equivalent to those published historically, with a 25% reduction in cochlear dose through use of IMRT.
Other groups have demonstrated that ototoxicity does not appear to develop in medulloblastoma patients if cochlear dose is kept to 43 Gy or less (Paulino, ASTRO, 2008). The IMRT technique described as part of the current study certainly accommodates this restraint, with average cochlear dose being approximately 50% of prescribed boost dose.
This dose reduction did appear to translate clinically, with 13% of patients developing grade 3 or 4 ototoxicity. This is compared to a 64% incidence of ototoxicity described with conventional radiotherapy to the entire posterior fossa (Paulino, Am J Clin Oncol, 2000).
Of course, long term follow-up will be essential to completely understanding risk-benefit ratios associated with various treatment techniques used for boost delivery in medulloblastoma. A theoretical increase in second malignant neoplasm risk may be present with use of IMRT, which results in low-dose irradiation being delivered to larger volumes of tissue when compared to three-dimensional conformal radiotherapy. Second malignant neoplasms are recognized to develop many years after primary cancer treatment, and follow-up of the population described in this study will be very important.
Although longer follow-up will be valuable for more complete assessment of the results presented here, this study demonstrates that tumor bed boost using IMRT is likely a safe alternative to posterior fossa boost for treatment of children with medulloblastoma. Overall survival rates and progression free survival rates do not appear to differ from historical controls, and IMRT results in decreased cochlear dose. This reduction in dose appears to translate to decreased ototoxicity clinically.
Oct 24, 2013 - Use of integrated intensity-modulated radiation therapy (IMRT) has increased more among urologists who have acquired ownership of IMRT services versus urologists who do not own such services, according to research published in the Oct. 24 issue of the New England Journal of Medicine.