Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Journal of Clinical Oncology, Vol 25, No 34 (December 1), 2007: pp. 5465-5470
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.11.1807
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kramer, K.
Right arrow Articles by Cheung, N.-K. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kramer, K.
Right arrow Articles by Cheung, N.-K. V.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Phase I Study of Targeted Radioimmunotherapy for Leptomeningeal Cancers Using Intra-Ommaya 131-I-3F8

Kim Kramer, John L. Humm, Mark M. Souweidane, Pat B. Zanzonico, Ira J. Dunkel, William L. Gerald, Yasmin Khakoo, Samuel D. Yeh, Henry W. Yeung, Ronald D. Finn, Suzanne L. Wolden, Steven M. Larson, Nai-Kong V. Cheung

From the Departments of Pediatrics, Nuclear Medicine, Neurosurgery, Pathology, and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Kim Kramer, MD, Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, 1275 York Ave, Box 429, New York, NY 10021; e-mail: kramerk{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose Tumors metastasizing to the CNS and leptomeninges (LM) are associated with significant mortality. We tested the toxicity, pharmacokinetics, and dosimetry of intraventricular iodine-131–labeled monoclonal antibody 3F8 (131I-3F8) targeting GD2-positive CNS/LM disease in a phase I clinical trial.

Patients and Methods Adequate CSF flow was determined by pretreatment indium-111-DTPA studies. Fifteen patients received a tracer (1 to 2 mCi) and therapeutic injection (10 to 20 mCi) of intra-Ommaya 131I-3F8. 131I-3F8 pharmacokinetics were studied by serial CSF and blood samplings. Dosimetry was based on pharmacokinetics and region of interest (ROI) analyses on whole-body gamma camera scans. Tumor response was determined by clinical, radiographic, and cytologic criteria.

Results Total absorbed CSF dose was 1.12 to 13.00 Gy by sampling and 1.00 to 13.70 Gy by ROI data. Average dosimetry ratio (Gy/mCi) of the therapy/tracer administration was 0.88 (± 0.58) and 1.08 (± 0.66) based on CSF pharmacokinetics and ROI analysis, respectively. CSF half-life by sampling was 3 to 12.9 hours. Toxicities included self-limited headache, fever, and vomiting. Dose-limiting toxicity was reached at the 20-mCi dose, when transient elevations in intracranial pressure and chemical meningitis were seen. Three of 13 assessable patients achieved objective radiographic and/or cytologic responses. No late toxicities have been seen in two patients who remain in remission off therapy for more than 3.5 years.

Conclusion Intra-Ommaya 131I-3F8 was generally well tolerated; the maximum-tolerated dose was 10 mCi. A high CSF-to-blood ratio was achieved. Tracer studies reliably predicted the therapeutic dose to the CSF. Radioimmunoconjugates targeting GD2 may have clinical utility in the treatment of CNS/LM malignancies.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
The CNS is a sanctuary site for cancer relapse, presenting as parenchymal or leptomeningeal (LM) metastases.1-3 Incidence is increasing, especially for patients with breast and lung cancer.4 For clinically evident disease, limited palliative options exist; median survival time is 4 to 14 months.2,5,6 Stereotactic radiosurgery, preoperative functional imaging, and image-guided neurosurgery have improved the success of aggressive palliative surgical resections.7,8 However, novel therapeutic agents to prevent or delay disease progression are needed.

Tumor-selective radioimmunotherapeutic (RIT) strategies may inhibit LM tumor growth.9-11 Systemic administration of tumor-specific monoclonal antibodies has proven useful in the detection and treatment of many tumors.12,13 GD2 expression has been demonstrated in neuroblastoma and primary CNS tumors; expression in normal organs is limited to nervous tissue. 3F8 is a murine immunoglobulin G3 antibody against GD2. Intravenous 3F8 has antitumor effects in patients with metastatic neuroblastoma.14 When radiolabeled with iodine-131 (131I), 3F8 demonstrates sensitive and specific imaging of neuroblastoma.15 We report the toxicities, pharmacokinetics, and dosimetry of intra-Ommaya 131I-3F8 in patients with CNS/LM metastases.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Antibody Preparation, Radiolabeling, and Quality Control
3F8 is raised in BALB/c mice and recognizes GD2. 3F8 was prepared under current good manufacturing procedures as required by the US Food and Drug Administration and purified by affinity chromatography. All lots passed sterility and rabbit pyrogen testing and were free of murine viruses and DNA contamination. 3F8 was labeled with 131I as previously described.13 131I-3F8 retains more than 60% immunoreactivity, has a mean trichloracetic acid precipitability of 92%, and a specific activity averaging 5 mCi/mg. For intrathecal administration, 131I-3F8 was diluted into 5% human serum albumin, filtered using a 0.22-µm filter, and administered within approximately 2 hours of iodination.

Clinical Protocol
Patients with a histologically confirmed diagnosis of a refractory GD2-positive LM malignancy were eligible. The activity of the underlying systemic tumor did not influence eligibility, although patients had to have a projected minimum life expectancy of 2 months without a rapidly deteriorating neurologic examination, absolute neutrophil count of more than 1,000/µL, platelet count of more than 50,000/µL, blood urea nitrogen of less than 30 mg/dL, serum bilirubin of less than 3.0 mg/dL, and serum creatinine of less than 2 mg/dL. Patients with prior monoclonal antibody treatments were not excluded. Patients had not received radiotherapy within 6 weeks and did not receive chemotherapy 3 weeks before or after injections. Patients with obstructive hydrocephalus were excluded. Informed consent was obtained according to institutional review board guidelines.

Pretreatment evaluation included physical examination, hematology and serum chemistries, thyroid function studies, CSF analysis, and magnetic resonance imagine (MRI) studies of the brain and spine. Although not mandatory, assays for serum human-antimouse antibodies (HAMA) were performed at baseline and 1 month after therapy when possible, as previously described.16 Patients were pretreated with a saturated solution of oral potassium iodide, levothyroxine, dexamethasone, and phenytoin or phenobarbital. Ommaya catheter patency and adequate CSF flow were confirmed by indium-111-DTPA studies.

Treatment Plan
Patients received an initial tracer of 1 to 2 mCi of 131I-3F8 for dosimetry followed by a second therapy injection 4 to 7 days later. Premedications included acetaminophen, morphine, lorazepam, and diphenhydramine. Patients were observed overnight as inpatients for all injections. Post-treatment evaluation included clinical status, vital signs, neurologic examination, blood for serum chemistries, and CBC weekly for 1 month. MRI (brain and spine) and CSF cytology were obtained approximately 1 month after treatment.

Dosimetry
The CSF radiation dose was estimated by two methods. In the first method, CSF samples were obtained before infusion and at 5, 10, and 30 minutes and approximately 1, 2, 5, 24, and 48 hours after infusion. Ten microliters of CSF were counted in an LKB Wallac well scintillation counter (LKB Instruments, Mt Waverly, Victoria, Australia) alongside a 131I standard. Counts per minute were entered into Excel (Microsoft, Redmond, WA) and converted to activity per gram decay corrected to the time of administration of the dose. Data was fitted to a dual exponential clearance model of the type:

Formula
In this case, A and B are the different half-lives associated with redistribution and clearance of the radiolabel from the CSF compartment. Integration of equation for Y(t) x exp[–0.693t/(8.04 x 24)] yields the cumulative activity in g·cGy/mCi·h, which, when multiplied by the equilibrium dose constant for 131I, yields the dose to the CSF.

In the second method, whole-body sweeps were performed at a constant camera speed of 10 and 15 cm/min using an ADAC dual-headed VERTEX gamma camera (ADAC Laboratories, Milpitas, CA). A known activity of 131I alongside the patient served as a calibration standard. Regions of interest (ROIs) were drawn around the spinal CSF for the posterior image at the three imaging time points after infusion. An attenuation correction (exp[+0.11 x d]) was performed, where d corresponds to the cord depth determined from the single-photon emission computed tomography or MRI data. CSF volume was estimated to be 140 mL, with 70 mL in the spinal column and 70 mL in the ventricles (scaled for patients < 3 years of age). Counts per minute were entered into Excel, and background and decay were corrected and converted to activity. Data were fitted to a single exponential clearance function, and the curve was integrated to yield a cumulative activity within the CSF compartment, divided by the CSF mass and multiplied by the equilibrium dose constant for 131I to yield the CSF dose. The calculated CSF radiation dose was divided by 2 to obtain the dose at the ventricle/brain interface. The conjugate image approach was used for activity quantitation within regions of the brain.17 This method uses the geometric mean counts from the anterior and posterior ROI projections identified on both images and corrects for attenuation by the patient separation at the appropriate level of the body. Activity was converted to absorbed dose estimates using the Medical Internal Radiation Dose methodology.18

Multiple serial blood samples were also obtained; 0.1 mL of plasma was pipetted into scintillation counting vials from each sample alongside a 131I standard. Counts per minute were entered into Excel, and decay and background were corrected and converted to activity per gram using count data from the 131I standard. These data were fitted to a rising and falling exponential function:

Formula
where A and B are the biologic half-lives for the blood uptake and clearance, respectively. Integration of equation for Y(t) yields the cumulative activity in g·cGy/mCi·h, which, when multiplied by the equilibrium dose constant for 131I, yields the dose for the administered amount.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Fifteen patients (ages 1 to 61 years; Table 1) were registered and treated. Two additional patients (one each with melanoma and rhabdoid tumor) were registered but not treated because of sudden deterioration. Nine patients were enrolled at dose level 1 (10 mCi), and eight patients completed the protocol. Two of these eight patients were enrolled on a compassionate single-patient basis because of age and lack of tissue availability for GD2 confirmation. Six patients completed dose level 2 (20 mCi).


View this table:
[in this window]
[in a new window]

  		Table 1. Patient Characteristics, Dose Administered, and Acute Toxicity

 
All patients had CSF flow throughout the subarachnoid space; interpatient variability in CSF flow dynamics was noted on baseline indium-111-DTPA studies implying variable CSF flow and resorption. For 10-mCi injections, acute adverse effects including grade 1 or 2 fever, headache, and vomiting were commonly seen in the first few hours after injection, generally resolving within 24 hours. Symptoms were generally self-limited and managed with acetaminophen, antiemetics, and/or narcotics. Acute increases in intracranial pressure were noted in two patients with pre-existing communicating hydrocephalus (patient 1 with melanoma, on re-treatment with a second 10 mCi, experienced altered mental status with increased intracranial pressure in the first few hours after injection, necessitating ventriculoperitoneal shunt placement approximately 72 hours later; patient 4 had elevated increased intracranial pressure with a grade 2 headache 2 days after the dosimetry injection that spontaneously resolved). After these observations, the decision was made to exclude patients with evidence of communicating hydrocephalus (magnetic resonance ventriculomegaly) on baseline MRI scans. At the 20-mCi dose, two patients encountered ≥ grade 3 dose-limiting toxicity (DLT). Patient 10 developed grade 4 fever, vomiting, and subsequent hyponatremia within 24 hours of injection and increased intracranial pressure at 36 hours. Patient 15 developed grade 3 symptoms of a chemical meningitis (fever, headache, nuchal rigidity, and CSF pleocytosis with negative cultures) 3 to 4 days after therapy. Both patients were managed with supportive medications, and symptoms resolved over 2 to 3 days (Table 1). DLT was seen in these two patients who received a CSF dose of 58.6 and 66.6 cGy/mCi, respectively. The maximum-tolerated dose was determined to be 10 mCi. Because these adverse effects developed within hours and were self-limited, DLTs were likely chemical in origin. Given the pretreatment sterility testing and the absence of pyrogen in the antibody preparation, acute adverse effects were attributed to 3F8. Myelosuppression was neither expected nor observed at the doses administered. No late toxicities have been seen, with the longest survivors off therapy and in remission for more than 3.5 years.

Pharmacokinetics and Dosimetry
The CSF counts/min were observed to undergo an initial rapid decline over the first hour as a result of antibody redistribution within the CSF, followed by a much slower decline associated with eventual clearance. The CSF biologic half-life ranged from 3 to 12.9 hours by CSF samples and from 7.2 to 13.1 hours by ROI gamma camera data. The mean CSF radiation dose was 5.50 Gy (range, 1.1 to 13 Gy) based on CSF samples and 4.90 Gy (range, 1 to 13.7 Gy) by ROI data. The CSF dose per millicurie of administered activity was 11.8 to 74.1 cGy/mCi (Table 2), where the mean estimated dose to the meninges, extrapolated from the total CSF dose, was 50% of the total CSF dose. Calculated radiation doses within focal areas of uptake ranged from 0.23 to 1.23 Gy/mCi by ROI quantitation. The average blood dose was 0.48 Gy (range, 0.14 to 1.1 Gy; 0.5 to 6.0 cGy/mCi; Table 2). Activity levels in the blood remained low (< 0.01% injected dose/mL), peaking at 12 to 48 hours. The activity in the CSF decreased much more rapidly than the physical half-life of 8 days; the concentration of the activity (uCi/mL) decreased by 2 orders of magnitude within 2 to 3 days after administration (Fig 1). Because biologic clearance was quite rapid, the dose contribution for the time interval of 72 hours to infinity was less than 10%. The radiation dose per administered activity (Gy/mCi) for each patient resulting from tracer and therapy injections was compared. The average ratio (± standard deviation), in Gy/MBq administered, of the therapy/tracer administration was 0.88 (± 0.58) and 1.08 (± 0.66) by CSF counting and ROI analysis, respectively. For patients 1, 2, 3, 6, 7, 10, 13, and 15, the therapy CSF dose estimates were within 20% of that predicted by the tracer examination. For other patients, discrepancies were observed in the predicted CSF tracer dose estimates and the actual calculated therapy dose delivered, in large part because of variable intrapatient CSF clearance. HAMA development was observed in three of five patients tested more than 1 month after treatment, although it seemed unlikely that HAMA played any role in the clearance of the therapy dose. No observed toxicity seemed related to HAMA reactivity.


View this table:
[in this window]
[in a new window]

  		Table 2. Dosimetry Data Comparing CSF Sampling to ROI Analyses (Gy)

 

Figure 1
View larger version (19K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 1. CSF clearance in patients after therapy dose.

 
Imaging Studies
131I-3F8 whole-body and single-photon emission computed tomography scans showed distribution throughout the subarachnoid space along the spinal cord down to the level of the cauda equina by 4 hours and progressively over the convexity by 24 and 48 hours (Fig 2). Focal areas of 131I-3F8 uptake were not observed for most patients, although retention of activity in the ventricles was evident at 24 and 48 hours in all patients. Nonuniform tracer distribution seemed to correspond more with variable CSF flow throughout the thecal sac rather than with nodularity or known tumor deposits on MRI.


Figure 2
View larger version (29K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 2. Serial whole-body posterior images of iodine-131–labeled monoclonal antibody 3F8 scans obtained at (A) 4 hours and (B) 24 hours after administration showing distribution throughout the thecal sac.

 
Clinical Response
Although not the primary study objective, evidence of tumor responses was recorded. Clinical response, namely decreased headaches, was noted in two patients (patients 1 and 3), accompanied by decreased LM enhancement on MRI (patient 1). Patient 11's CSF was cleared of malignant neuroblastoma cells, but this patient had a new spinal nodule on MRI 1 month later. She remained alive with disease for 23 months after 131I-3F8 before dying of progressive neuroblastoma. Patient 13 experienced clearance of the CSF of malignant primitive neuroectodermal tumor cells and has remained in complete remission off further therapy with negative CSF cytology by Ommaya and lumbar puncture on multiple samplings for more than 45 months; resolution of three areas of enhancement on MRI was also noted. Patient 14 had an isolated CNS relapse of neuroblastoma. He was treated with surgery, chemotherapy, craniospinal irradiation, and both intraventricular 131I-3F8 and intravenous 3F8. He now remains in complete remission off all therapy nearly 4 years since CNS relapse. This remission is notable given our previous experience, where the median survival time for patients with relapsed CNS neuroblastoma was 5.5 months despite surgery, high-dose salvage chemotherapy, and/or conventional external-beam radiation therapy.2


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
More effective therapies are needed to decrease the CNS cancer morbidity and mortality. Preliminary results from various studies using intrathecal RIT in children and adults have been favorable.19-25 Brown et al22 reported the administration of 40 to 100 mCi 131I-antitenascin monoclonal antibody 81C6 in 31 patients with no grade 3 or 4 nonhematologic toxicities. The calculated regional radiation absorbed doses were 19 to 33 Gy, which are similar to the CSF doses estimated in this study. Targeting the same antigen, Reardon et al26,27 reported an improved median survival for patients with newly diagnosed and recurrent malignant glioma after 120 mCi and 100 mCi of intracavitary 131I-m81C6, respectively. Objective responses and improved mean survival have been reported.20-24 Particularly relevant to the increasingly large population of patients with LM carcinomatosis from metastatic breast cancer is a recent report documenting effective and well-tolerated administration of intrathecal trastuzumab.28 With the lack of effector cells and complement in the CSF, radiolabeled monoclonal antibodies have a distinct advantage over naked antibodies. In our phase I study, 10 mCi per injection seemed to be safe, and clinical, radiographic, and cytologic responses were observed, with the longest being in two patients now more than 3.5 years in remission. A high therapeutic radiation dose to the CSF was delivered by a single injection of 10 to 20 mCi 131I-3F8. The dose to the CSF was used as a predominant surrogate for tumor cell dose for free floating tumor cells in the CSF; anticipated dose to LM tumor deposits are substantial when considering preferential tumor uptake and geometric enhancement factors.17,29,30 We recognize the difficulty in quantifying radiation dosimetry to lesions or tumor deposits less than 12 mm because of the limitations of the gamma camera. However, animal studies have shown that the radioactivity area under the curve ratios for tumor deposits versus CSF range from 5 for melanoma to more than 30 for neuroblastoma.25 The uptake on tumor cells is driven by the fact that the antibody is immunoreactive, and B/F = K[Ag] –b[Ab], where B is fraction bound, F is fraction free, K is binding affinity of the antibody for GD2 antigen, b is the fraction of bound antibody, and [Ab] is the total concentration of antibody in the CSF. This assumes equilibrium conditions and 100% antibody immunoreactivity. Therefore, CSF radiation dose estimates presented in this study represent a minimum dose received by free floating tumor cell deposits. Because the tumor is likely to be seeding the meninges, the dose estimated at the cord surface is another surrogate marker that can be used to estimate meningeal tumor uptake.17 A large therapeutic window between effective tumor cell ablation and the dose received to normal brain, spinal cord, and blood is anticipated.

Although not applicable to this patient population who did not receive multiple serial injections, the presence of HAMA could induce a faster clearance in the systemic circulation and decrease the bystander dose to the blood. Because of the blood-brain barrier, systemic production of HAMA is associated with low titers in the CSF, namely a 14- to 22-fold difference of HAMA in the CSF versus the blood.29 In the presence of systemic HAMA, repetitive injections of intrathecal 131I-3F8 are expected to deliver comparable doses of radiation to the CSF space but with even more rapid systemic clearance, thereby reducing systemic toxicity. We have recently observed this hypothesis to be true, whereby multiple serial injections of intrathecal 131I-3F8 are administered as part of a phase II study (unpublished data), along with HAMA levels before each treatment injection. This observation is critical because myelosuppression is a DLT of many RIT trials.

As with other novel immunotherapeutic approaches using monoclonal antibodies or recombinant interleukin-2,11,31,32 acute toxicity is considerable but manageable. A high incidence of aseptic meningitis21 and increased intracranial pressure31,32 was noted and attributed to the introduction of antibody into the CSF. We recognize the limitations posed by both the isotope 131I and the relative restricted tumor expression of GD2 (neuroblastoma and medulloblastoma) in furthering the therapeutic application of 131I-3F8. As an alpha particle nanogenerator, actinium-225 (225Ac) -3F8 is a novel, highly potent, and selective anticancer drug. Intrathecal 225Ac-3F8 in a nude rat xenograft model of meningeal carcinomatosis significantly improved survival. Studies in nonhuman primates have shown encouraging results.33,34 Monkeys injected with one to three doses of intrathecal 225Ac-3F8 (80 to 150 kBq/kg total dose) did not demonstrate clinical or chemical toxicities. In addition, a more pan-specific tumor antibody would provide for broader application of intrathecal RIT. We have recently developed the murine monoclonal antibody 8H9.35,36 8H9 recognizes a unique glycoprotein homogeneously distributed on the cell membrane of a broad spectrum of pediatric and adult solid tumors of neuroectodermal, mesenchymal, and epithelial origin; normal tissue expression is restricted. 8H9 radiolabeled with 125I or 131I retains its immunoreactive properties. It can specifically target solid tumors, allowing the delivery of radiation or other therapeutic agents, sparing normal tissues. We are currently completing a phase I study of intrathecal 131I-8H9 for patients with refractory or recurrent high-risk CNS/LM tumors.

In conclusion, 131I-3F8 may be added to the armamentarium of modalities targeting GD2-expressing LM neoplasms. Phase II studies using serial injections of 10 mCi are underway to determine efficacy and as an additional treatment modality for patients with newly diagnosed medulloblastoma.


   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 REFERENCES
 
The author(s) indicated no potential conflicts of interest.


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
REFERENCES
 
Conception and design: Kim Kramer, John L. Humm, Suzanne L. Wolden, Steven M. Larson, Nai-Kong V. Cheung

Financial support: Kim Kramer, Steven M. Larson, Nai-Kong V. Cheung

Administrative support: Kim Kramer, John L. Humm, Mark M. Souweidane, Pat B. Zanzonico, William L. Gerald, Samuel D. Yeh, Henry W. Yeung, Ronald D. Finn, Steven M. Larson, Nai-Kong V. Cheung

Provision of study materials or patients: Kim Kramer, John L. Humm, Mark M. Souweidane, Ira J. Dunkel, Yasmin Khakoo, Samuel D. Yeh, Henry W. Yeung, Ronald D. Finn, Steven M. Larson, Nai-Kong V. Cheung

Collection and assembly of data: Kim Kramer, John L. Humm, Pat B. Zanzonico, Suzanne L. Wolden, Nai-Kong V. Cheung

Data analysis and interpretation: Kim Kramer, John L. Humm, Pat B. Zanzonico, Ira J. Dunkel, William L. Gerald, Suzanne L. Wolden, Steven M. Larson, Nai-Kong V. Cheung

Manuscript writing: Kim Kramer, John L. Humm, Mark M. Souweidane, Pat B. Zanzonico, Ira J. Dunkel, Yasmin Khakoo, Suzanne L. Wolden, Nai-Kong V. Cheung

Final approval of manuscript: Kim Kramer, John L. Humm, Mark M. Souweidane, Pat B. Zanzonico, Ira J. Dunkel, William L. Gerald, Yasmin Khakoo, Samuel D. Yeh, Henry W. Yeung, Ronald D. Finn, Suzanne L. Wolden, Steven M. Larson, Nai-Kong V. Cheung


   ACKNOWLEDGMENTS
 
We acknowledge the Memorial Sloan-Kettering Cancer Center attending staff, fellows, residents, and nurses who provided exceptional patient care. We are particularly indebted to Ester Dantis, NP, for her expertise and Shakeel Modak, MD, for critical review of this manuscript. We are grateful to the Ludwig Center for Immunotherapy for infrastructure support for this study.


   NOTES
 
Supported by National Cancer Institute Grant No. CA72868, the Robert Steel Foundation, Catie Hoch Foundation, Katie's Find A Cure Fund, Pediatric Cancer Foundation, and The Leptomeningeal Research Fund.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Kesari S, Batchelor TT: LM metastases. Neurol Clin 21:25-66, 2003[CrossRef][Medline]

2. Kramer K, Kushner BH, Cheung NKV: Neuroblastoma metastatic to the central nervous system: The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 91:1510-1519, 2001[CrossRef][Medline]

3. Gilbert MR: Neoplastic meningitis: A unique disease process or a "test tube" for evaluating cancer treatments? Curr Oncol Rep 5:11-14, 2003[CrossRef][Medline]

4. Taillibert S, Donadey FL, Chodkiewicz C, et al: LM metastases from solid malignancy: A review. J Neurooncol 75:85-99, 2005[CrossRef][Medline]

5. Shaw PJ: Neuroblastoma with intracranial involvement: An ENSG study. Med Pediatr Oncol 20:149-155, 1992[CrossRef][Medline]

6. Kellie JJ, Hayes A, Bowman L, et al: Primary extracranial neuroblastoma with central nervous system metastases: Characterization by clinicopathologic findings and neuroimaging. Cancer 68:1999-2006, 1991[Medline]

7. Flickinger JC: Radiotherapy and radiosurgical management of brain metastases. Curr Oncol Rep 3:484-489, 2001[CrossRef][Medline]

8. Weinberg JS, Lang FF, Sawaya R: Surgical management of brain metastases. Curr Oncol Rep 3:476-483, 2001[CrossRef][Medline]

9. Kramer K, Cheung NKV, Humm JL, et al: Targeted radioimmunotherapy for leptomeningeal cancer using (131)I-3F8. Med Pediatr Oncol 35:716-718, 2000[CrossRef][Medline]

10. Bergman I, Barmada MA, Heller G, et al: Treatment of neoplastic meningeal xenografts by intraventricular administration of an anti-ganglioside monoclonal antibody 3F8. Int J Cancer 82:538-548, 1999[CrossRef][Medline]

11. Bigner DD, Brown MT, Friedman AH, et al: Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: Phase I trial results. J Clin Oncol 16:2202-2212, 1998[Abstract]

12. Lundin J, Osterborg A, Brittinger G, et al: CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: A phase II multicenter study—European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin's Lymphoma. J Clin Oncol 16:3257-3263, 1998[Abstract]

13. Cheung NKV, Landmeier B, Neely J, et al: Complete tumor ablation with iodine-131-radiolabeled disialoganglioside GD2 specific monoclonal antibody against human neuroblastoma xenografted in nude mice. J Natl Cancer Inst 77:739-745, 1986[Medline]

14. Cheung NK, Kushner BH, Cheung IY, et al: Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 16:3053-3060, 1998[Abstract/Free Full Text]

15. Yeh SD, Larson SM, Burch L, et al: Radioimmunodetection of neuroblastoma with 131I-3F8: Correlation with biopsy, iodine-131-metaiodobenzylguanidine and standard diagnostic modalities. J Nucl Med 32:769-776, 1991[Abstract/Free Full Text]

16. Cheung NKV, Cheung IY, Canete A, et al: Antibody response to murine anti-GD2 monoclonal antibodies: Correlation with patient survival. Cancer Res 54:2228-2233, 1994[Abstract/Free Full Text]

17. Hammond ND, Moldofsky PJ, Beardsley MR, et al: External imaging techniques for quantitation of distribution of I-131 F(ab')2 fragments of monoclonal antibody in humans. Med Phys 11:78-83, 1984[CrossRef][Medline]

18. Loevinger R, Budinger TF, Watson EE: MIRD Primer for Absorbed Dose Calculations. Revised Edition. New York, NY, The Society of Nuclear Medicine Inc, 1991

19. Lashford LS, Davies AG, Richardson RB, et al: A pilot study of 131-I-monoclonal antibodies in the therapy of leptomeningeal tumors. Cancer 61:857-868, 1988[Medline]

20. Moseley RP, Davies AG, Richardson RB, et al: Intrathecal administration of 131-I-radiolabelled monoclonal antibody as a treatment for neoplastic meningitis. Br J Cancer 62:637-642, 1990[Medline]

21. Kemshead JT, Papanastassiou V, Coakham B, et al: Monoclonal antibodies in the treatment of central nervous system malignancies. Eur J Cancer 28:511-513, 1992[CrossRef][Medline]

22. Brown MT, Coleman E, Friedman AH, et al: Intrathecal 131-I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: Phase I trial results. Clin Cancer Res 2:963-972, 1996[Abstract]

23. Bigner DD, Brown M, Coleman RE, et al: Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131-I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Mel-14 F (ab') 2: A preliminary report. J Neurooncol 24:109-122, 1995[CrossRef][Medline]

24. Coakham HB, Kemshead JT: Treatment of neoplastic meningitis by targeted radiation using 131-I-radiolabelled monoclonal antibodies: Results of responses and long term follow up in 40 patients. J Neurooncol 38:225-232, 1998[CrossRef][Medline]

25. Bergman I, Pohl CR, Venkataramanan R, et al: Intrathecal administration of an anti-ganglioside antibody results in specific accumulation within meningeal neoplastic xenografts in nude rats. J Immunother 22:114-123, 1999[Medline]

26. Reardon DA, Akabani G, Coleman RE, et al: Phase II trial of murine 131-I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20:1389-1397, 2002[Abstract/Free Full Text]

27. Reardon DA, Akabani G, Coleman RE, et al: Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary or metastatic malignant brain tumors: Phase II study results. J Clin Oncol 24:115-122, 2006[Abstract/Free Full Text]

28. Stemmler HJ, Schmitt M, Harbeck N, et al: Application of intrathecal trastuzumab (Herceptin) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer. Oncol Rep 15:1373-1377, 2006[Medline]

29. Kramer K, Cheung NKV, Humm JL, et al: Pharmacokinetics and acute toxicology of intraventricular 131-I-monoclonal antibody targeting disialoganglioside in non-human primates. J Neurooncol 35:101-111, 1997[CrossRef][Medline]

30. Humm JL, Cobb LM: Nonuniformity of tumor dose in radioimmunotherapy. J Nucl Med 31:75-83, 1990[Abstract/Free Full Text]

31. Herrlinger U, Buchholz R, Jachimczak P, et al: Intrathecal treatment of C6 glioma leptomeningeal metastasis in Wistar rats with interleukin-2. J Neurooncol 27:193-203, 1996[CrossRef][Medline]

32. Fathallah-Shaykh HM, Zimmerman C, Morgan H, et al: Response of primary leptomeningeal melanoma to intrathecal recombinant interleukin-2: A case report. Cancer 77:1544-1550, 1996[Medline]

33. Miederer M, McDevitt MR, Borchardt P, et al: Treatment of neuroblastoma meningeal carcinomatosis with intrathecal application of alpha-emitting atomic nanogenerators targeting disialo-ganglioside GD2. Clin Cancer Res 10:6985-6992, 2004[Abstract/Free Full Text]

34. Miederer M, McDevitt MR, Sgouros G, et al: Pharmacokinetics, dosimetry, and toxicity of the targetable atomic generator, 225Ac-HuM195, in nonhuman primates. J Nucl Med 45:129-137, 2004[Abstract/Free Full Text]

35. Modak S, Kramer K, Gultekin SH, et al: Monoclonal antibody 8H9 targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors. Cancer Res 61:4048-4054, 2001[Abstract/Free Full Text]

36. Modak S, Gerald W, Cheung NKV: Disialoganglioside GD2 and a novel tumor antigen: Potential targets for immunotherapy for desmoplastic small round cell tumor. Med Pediatr Oncol 39:547-551, 2002[CrossRef][Medline]

Submitted March 13, 2007; accepted July 26, 2007.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Neuro OncologyHome page
I. J. Dunkel, S. L. Gardner, J. H. Garvin Jr, S. Goldman, W. Shi, and J. L. Finlay
High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma
Neuro Oncology, January 11, 2010; (2010) nop031v1.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
Y. Lv, N.-K. V. Cheung, and B. M. Fu
A Pharmacokinetic Model for Radioimmunotherapy Delivered Through Cerebrospinal Fluid for the Treatment of Leptomeningeal Metastases
J. Nucl. Med., August 1, 2009; 50(8): 1324 - 1331.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kramer, K.
Right arrow Articles by Cheung, N.-K. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kramer, K.
Right arrow Articles by Cheung, N.-K. V.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online