Three-year recurrence-free survival in a patient with recurrent medulloblastoma after resection, high-dose chemotherapy, and intrathecal Yttrium-90-labeled DOTA0-D-Phe1-Tyr3-octreotide radiopeptide brachytherapy

Authors


Abstract

BACKGROUND

Most medulloblastomas express high levels of somatostatin type 2 receptors (sst2). DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC) specifically binds sst2 in the low nanomolar range. The cytotoxic effect is mediated by the chelated, β-emitting, metallic radionuclide Yttrium 90 (90Y). The authors applied this innovative treatment option in a boy age 8 years who presented with a recurrent medulloblastoma of the cauda equina: a prognostically poor condition. Targeted radiotherapy was administered to treat minimal sst2-expressing tumor remnants, which persisted despite conventional and high-dose chemotherapy and intercurrent resection of the lesion.

METHODS

A medulloblastoma arising from the floor of the fourth ventricle had been removed surgically; then, the patient was treated with standard adjuvant chemotherapy and craniospinal irradiation according to the prospective HIT '91 protocol. Complete remission was achieved for 20 months, when a drop metastasis of the cauda equina manifested with sensorimotor lumbosacral deficits and urinary incontinence. After four cycles of neoadjuvant chemotherapy (which consisted of combined ifosfamide, carboplatinum and etoposide), two cycles of high-dose chemotherapy and autologous stem cell transplantation were performed; in between, the responding residual tumor within the lumbosacral nerve fibers was microscopically removed. Thereafter, an Indium-111-DOTATOC test injection indicated sst2-expressing tumor remnants within the cauda equina. Con- sequently, 4 cycles of [90Y]-DOTATOC (4 × 562.5 megabecquerels) were injected directly into the cerebrospinal fluid in monthly intervals.

RESULTS

The consolidating intrathecal brachytherapy using [90Y]-DOTATOC was tolerated well. A complete remission was achieved for a 3-year period. The only remaining deficit was urinary incontinence.

CONCLUSIONS

Intrathecal administration of targeted radiopeptide brachytherapy in combination with conventional and high-dose chemotherapy and surgical removal represents a promising new option to treat recurrent medulloblastoma and should be explored further. Cancer 2005. © 2005 American Cancer Society.

We report on the first successful application of targeted β-irradiation to a recurrent medulloblastoma using Yttrium 90 (90Y)-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC), which specifically binds to somatostatin type 2 receptors (sst2). Medulloblastomas consistently express high levels of sst2.1 Initially, a boy age 8 years presented with headache and early morning emesis for 5 weeks. Physical examination revealed a vestibuloocular nystagmus and bilateral papilledema. A large vermian tumor mass that measured 4.5 cm in greatest dimension was detected on the magnetic resonance image (MRI) in intimate contact with the floor of the fourth ventricle and extending into the superior medullary velum. In addition, the cerebrospinal fluid outflow from the fourth ventricle to the basal cisterns was blocked, leading to an occlusive hydrocephalus. External ventricular drainage of the right frontal horn was performed, followed by suboccipital craniectomy. Because of adherence to the floor of the fourth ventricle, the tumor could not be removed completely. Histopathologic analysis revealed a medulloblastoma characterized by large nuclei, Homer–Wright rosettes, positive staining for synaptophysin, and negative staining for glial fibrillary acidic protein (GFAP). The tumor was classified as Chang Stage T3B. Chemotherapy and external beam-radiotherapy were applied according to the German prospective randomized trial HIT '91.2 Craniospinal irradiation was performed with a dose of 55.2 grays (Gy) and 35.2 Gy, respectively. The follow-up MRI did not show any evidence of residual tumor.

Twenty months after the completion of treatment, the boy developed signs of bladder dysfunction, culminating in acute urinary retention. Neurologic examination revealed a moderately severe cauda-equina syndrome with polyradicular sensorimotor deficits. The MRI showed an oval-shaped mass measuring 5.5 cm in length between lumbar vertebra 5 and sacral segment 4 (Fig. 1A,B).

Figure 1.

Intrathecal, targeted, radiopeptide brachytherapy for recurrent medulloblastoma after conventional and high-dose chemotherapy and resection. (A,B) Axial lumbosacral magnetic resonance imaging (MRI) scans show a large intradural mass within the cauda equina. The drop metastasis manifested 20 months after standard treatment of a posterior fossa medulloblastoma, which had led to a complete remission. Immunohistochemical detection of somatostatin type 2 (sst2) receptors in tumor tissue using the R2-88 antibody. (C) Strong staining of sst2-positive tumor cells (scale bar = 0.1 mm). (D) Lack of immunostaining after preabsorption with peptide antigen. (E) Planar scintigraphy 24 hours after intrathecal injection of the diagnostic tracer 111In-DOTA0-D-Phe1-Tyr3-octreotide shows a strong signal of the sst2-positive caudal drop metastasis. (F) A sagittal MRI scan of the lumbosacral spine proves absence of residual tumor tissue 3 years after manifestation of the spinal medulloblastoma recurrence.

Conventional chemotherapy with four cycles of ifosfamide, carboplatinum, and etoposide resulted in a partial regression of < 50% of the tumor volume. Thereafter, two courses of high-dose chemotherapy (HDC) were administered, the first consisted of thiotepa and etoposide, and the second—16 weeks later—consisted of cyclophosphamide and melphalan. Each course was followed by autologous peripheral stem cell transplantation. Between the two HDC courses, the residual tumor mass was removed surgically. Histopathologic examination disclosed vital medulloblastoma tissue, which, immunohistochemically,3 expressed high levels of sst2 (Fig. 1C,D). Recovery was uneventful.

Two months after the second course of HDC, intrathecal injection of the γ-tracer Indium-111 (111In)-DOTATOC yielded a scintigraphically suspicious structure within the cauda equina (Fig. 1E), indicating residual sst2-positive tumor tissue. The planar scintigram of the abdomen showed, within the dural sac, the neoplastic lesion below kidney and spleen, which also retain octreotide-based vectors. Consequently, 4 cycles of low dose-rate β-irradiation with [90Y]-DOTATOC were administered intrathecally in monthly intervals after informed consent had been obtained from the parents of the child. The cumulative, intrathecally injected activity amounted to 2250 megabecquerels (MBq) and was tolerated well. However, urinary bladder dysfunction did not improve and required permanent external drainage. To date, follow-up examinations and MRI scans over a 3-year period have not shown any evidence of residual tumor (Fig. 1F). Thus, a lasting complete remission was obtained in a child with early recurrent medulloblastoma.

IMMUNOHISTOCHEMISTRY

Formalin fixed medulloblastoma tissue was stained according to a standard protocol.3 The R2-88 antibody, which kindly was provided by Dr. A. Schonbrunn (Houston, TX), was used for the detection of sst2 receptors. Strong brown labeling was indicative of sst2-positive tumor cells. In control sections, immunostaining followed preabsorption of peptide antigen.

Scintigraphy

Planar scintigraphic images of the head and the abdomen were obtained with a large-field-of-view camera (DIACAM; Siemens), as described previously.4 Images were acquired 30 minutes, 4 hours, 24 hours, 48 hours, and 72 hours after intrathecal injection of 112.5 MBq 111In-labeled DOTATOC.

DISCUSSION

Medulloblastoma is the most frequent embryonal tumor of the central nervous system (CNS), with an incidence of 0.2–0.6 per 100,000 children annually and a male predominance (65%).5 The median patient age at diagnosis of medulloblastoma is 9 years, with 2 age peaks at 2–4 years and 6–8 years. Surgery, chemotherapy, and irradiation of the craniospinal axis represent the mainstay of treatment for primary medulloblastoma of the posterior fossa. However, several studies have shown severe impairment of neurocognitive functions after radiotherapy, particularly in children age < 4 years, with increased disabilities in learning and concentration and with lower intelligence scores compared with sibling controls.6, 7 Because of these disadvantages, young children initially may be treated with chemotherapy to prevent or delay irradiation.8 In a large, multicenter, randomized study, Taylor et al. demonstrated that chemotherapy prior to radiotherapy improved event-free survival compared with radiotherapy alone in patients with Chang Stage M0–M1 medulloblastoma.9 However, only 50–60% of children who are affected by this disease can be expected to be alive and free of tumor progression 5 years after diagnosis.10, 11 The recurrence rate for medulloblastoma is 30–40%, and recurrences are located either on the primary tumor site or along the cerebrospinal fluid pathways. Recurrence outside of the CNS is very rare.5 The mean survival of patients with recurrent medulloblastoma is short, and only 20–30% of patients survive > 1 year.12 It is evident that more efficient therapeutic modalities must be developed for patients with recurrent medulloblastoma.

Based on the experience of this first patient, targeted radiopeptide brachytherapy may represent a promising additional treatment modality for recurrent medulloblastoma when combined with surgery, conventional chemotherapy, and HDC. This nontoxic approach is tolerated well and exploits the fact that most medulloblastomas constitutively express sst2 receptors.1 In fact, this tumor expressed high levels of sst2 receptors (Fig. 1C,D). Intrathecal test injection of the diagnostic tracer [111In]-DOTATOC induced a strong and persistent signal of the residual spinal drop metastasis (Fig 1E). This suggested sst2-positive residual tumor tissue, despite conventional chemotherapy, HDC, and microsurgical removal of the lesion. To treat persisting microscopic disease, we decided also to deliver targeted radiotherapy. Subsequently, 4 × 562.5 MBq of 90Y-DOTATOC were injected directly into the cerebrospinal fluid. This was tolerated well. Because the radiopharmakon is distributed in the entire subarachnoid space, it potentially may eradicate microscopic tumor cell clusters, which may be disseminated throughout the entire subarachnoid space. In this instance, surgical exploration of the cauda equina and tumor removal between two cycles of HDC showed that a significant amount of vital residual tumor tissue still remained after the first cycle of HDC. Therefore, extensive resection of this large spinal drop metastasis, initially measuring 5.5 cm in greatest vertical dimension, represents an additional critical factor for the long disease-free period obtained in this patient. The importance of the extent of surgical removal is well documented for primary medulloblastoma of the posterior fossa, in which residual tumor measuring < 1.5 cm2 is associated with a significantly better prognosis.13 This principle is likely also to apply to recurrent medulloblastoma at distant sites. For tumor targeting, we used the somatostatin analogue DOTATOC, which shows high affinity for sst2 receptors in the low nanomolar range.14 Octreotide analogues have been tested successfully in vitro using medulloblastoma xenografts.15 The modified octreotide DOTATOC is very stable metabolically, is hydrophilic, and is labeled efficiently with the metallic radionuclides 111In and 90Y. This peptidic targeting vector previously was used successfully in the treatment of neuroendocrine tumors16, 17 and primary brain tumors of glial origin.4, 18, 19, 20

HDC with consecutive autologous stem cell transplantation represents a promising treatment option for patients with recurrent medulloblastoma.21 The rationale for this modality is based on the sensitivity of brain tumors to cytotoxic agents that have hematopoietic dose-limiting toxicity. Feasibility of HDC with stem-cell rescue has been reported for some CNS malignancies and advanced, non-CNS malignancies that are associated with a relatively poor prognosis.22, 23 In adults, HDC demonstrated better results than conventional chemotherapy in recurrent medulloblastoma.12 In young children, HDC may be investigated to replace craniospinal irradiation as prophylaxis against CNS metastasis.24 Moreover, in primary medulloblastomas, it was found that the combination of surgery, craniospinal irradiation, and HDC was promising, resulting in a 2-year progression-free survival rate of 73% for high-risk patients.25

In conclusion, targeting sst2-positive, recurrent medulloblastoma with [111I]-DOTATOC for diagnosis of spinal dissemination and with [90Y]-DOTATOC for subsequent intrathecal treatment represents a potentially useful, new, diagnostic and therapeutic modality for this critical condition. Radiopeptide brachytherapy, however, may need to be combined with HDC and surgical removal of the tumor mass to achieve lasting responses. Determining the role of [90Y]-DOTATOC in recurrent, receptor-positive medulloblastoma will require further evaluation.

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