Intraventricular Chemotherapy Research Articles

Ommaya reservoir use in pediatric ALL and NHL: a review at St. Jude Children's Research Hospital.

The intraventricular route of chemotherapy administration, via an Ommaya Reservoir (OmR) improves drug distribution in the central nervous system (CNS) compared to the more commonly used intrathecal administration. We retrospectively reviewed our experience with intraventricular chemotherapy, focused on methotrexate, in patients with Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL). Twenty-four patients (aged 7 days - 22.2 years) with 26 OmR placements were identified for a total of 25,009 OmR days between 1990 and 2019. Methotrexate cerebrospinal fluid (CSF) concentrations (n = 124) were analyzed from 59 courses of OmR therapy in 15 patients. Twenty-one courses involved methotrexate dosing on day 0 only, whereas 38 courses involved booster dosing on days 1, 2, or both. We simulated the time CSF methotrexate concentrations remained > 1 µM for 3 days given various dosing regimens. CSF methotrexate exposure was higher in those who concurrently received systemic methotrexate than via OmR alone (p < 10- 7). Our simulations showed that current intraventricular methotrexate boosting strategy for patients ≥ 3 years of age maintained CSF methotrexate concentrations ≥ 1 µM for 72h 40% of the time. Alternatively, other boosting strategies were predicted to achieve CSF methotrexate concentrations ≥ 1 µM for 72h between 46 and 72% of the time. OmR were able to be safely placed and administer intraventricular methotrexate with and without boost doses in patients from 7 days to 22 years old. Boosting strategies are predicted to increase CSF methotrexate concentrations ≥ 1 µM for 72h.

SURG-44. VENTRICULAR CEREBROSPINAL FLUID SAMPLING IN PEDIATRIC DIFFUSE MIDLINE GLIOMA PATIENTS: INSTITUTIONAL EXPERIENCE AND REVIEW OF THE LITERATURE

Abstract BACKGROUND Increasing evidence suggests that circulating biomarkers may serve diagnostic and longitudinal monitoring purposes in pediatric neuro-oncology. Mutant tumor DNA is detectable in the cerebrospinal fluid (CSF) of pediatric diffuse midline glioma (DMG) patients and quantity can reflect disease burden. CSF sampling (“liquid biopsy”) via a CSF access device could therefore play a role in DMG management. Therefore, we set to evaluate the incidence of hydrocephalus (HCP) in DMG patients, and to characterize ventricular reservoir placement and access practices. METHODS A single institution retrospective review of DMG patients &amp;lt;21-years-old was performed (1984-2019). MEDLINE searches for reports of ventricular reservoir or shunt placement in DMG, and reservoir access for intraventricular chemotherapy (IVC) were performed. RESULTS At our institution, 62.6% of DMG patients (67/108) required intervention for HCP: 19.4% provided transient CSF access (ETV alone n = 3, EVD n = 8, unspecified n = 2), and 80.6% permanent CSF access (ETV + reservoir n = 13, shunt n = 41). Further, 22/34 patients with initially transient CSF devices required conversion to a permanent device. Five devices were revised for malfunction, one for infection. Seventeen articles cited HCP in 22% to 100% of DMG patients. IVC administration was described in 632 patients (seven articles), with 42 infectious and 63 non-infectious complications. CONCLUSIONS Management of HCP is often necessary in children with DMG. Given the low rate of clinical risk associated with VAD placement and access, and the potential utility of longitudinal disease monitoring via CSF analysis, VAD placement could be considered in future clinical trials to guide DMG treatment.

527P Efficacy of intraventricular chemotherapy with pemetrexed for leptomeningeal metastasis from lung adenocarcinoma: A retrospective study

527P Efficacy of intraventricular chemotherapy with pemetrexed for leptomeningeal metastasis from lung adenocarcinoma: A retrospective study

P16.05.B SAFETY AND EFFICACY OF INTRA-CSF BIOLOGIC AGENTS IN TREATMENT OF NEOPLASTIC MENINGITIS

Abstract BACKGROUND Neoplastic meningitis (NM) is an increasingly frequent, profoundly morbid, and almost invariably fatal complication of solid and hematologic malignancies. Despite multimodal therapy, median survival in randomized trials is approximately 4 months. Biologic agents are widely utilized in management of extra-CSF disease, but often have limited ability to penetrate the CSF. Intra-CSF administration of biologic agents has not been widely investigated. We describe the safety and efficacy of tumor-specific, intra-CSF biologic therapy in a large group of patients with neoplastic meningitis. MATERIAL AND METHODS We queried the database of a large, international neoplastic meningitis registry (NeMeRe) to identify patients with neoplastic meningitis who received at least one dose of neoplastic meningitis-directed therapy with a biologic agent. Detailed patient demographic, treatment, toxicity and outcome data was extracted and analyzed for the first 140 consecutive patients treated at our institution. RESULTS These 140 patients received an intrathecal biologic agent as part of a histology- and molecular profile-directed intraventricular chemotherapy treatment approach. Agents included rituximab (58 patients with lymphoma, 224 cycles), trastuzumab (42 patients with malignant primary brain tumors, 211 cycles; 15 patients with breast cancer, 149 cycles; 1 patient with esophageal cancer, 9 cycles), panitumumab (4 patients with lung cancer, 9 cycles), nivolumab (1 patient with melanoma, 5 cycles; 2 patients with breast cancer, 2 cycles; 2 patients with GBM 12 cycles; 2 patients with lung cancer, 4 cycles; 2 patients with gastric adenocarcinoma, 17 cycles; 2 patients with renal clear cell carcinoma, 17 cycles; 1 patient with AML, 2 cycles; 1 patient with multiple myeloma, 8 cycles) and alpha-interferon (10 patients with melanoma, 31 cycles; 2 patients with renal clear cell carcinoma, 18 cycles). Grade I/II toxicity occurred in 5.8% of rituximab, 3.2% of trastuzumab, 0% of panitumumab, 16.3% of nivolumab, and 3.2% of alpha-interferon containing cycles. There was no grade III toxicity. Median survivals in patients with lymphomatous meningitis (304 days), solid tumor NM from primary brain tumors (243 days), HER2 -positive breast cancer (not reached, &amp;gt;315 days), lung cancer (192 days), and melanoma (307 days) were encouraging. No difference in survival was seen between patients with and without treatment-related toxicity in any histologic group. CONCLUSION This large registry-based cohort study suggests that rituximab, trastuzumab, panitumumab, nivolumab, and alpha interferon may be safely administered into the CSF as part of a multi-agent intra-CSF treatment regimen. Survival, while very tentative, is encouraging. A prospective, multi-center evaluation of these agents in patients with neoplastic meningitis is warranted.

OUTC-06. BEST PRACTICES FOR THE SUCCESSFUL ADMINISTRATION OF COMBINATION METRONOMIC ANTI-ANGIOGENIC AND INTRAVENTRICULAR THERAPY

Abstract BACKGROUND Combination metronomic anti-angiogenic and intraventricular therapy incorporates a customized administration of a five-drug oral antiangiogenic regimen with intravenous bevacizumab and intraventricular chemotherapy and is an effective treatment regimen for children with recurrent central nervous system embryonal tumors. This treatment can be administered while maintaining quality of life and avoiding severe side effects through personalized therapy schedules; however, dosing modifications, available dosage formulations, and complexity of medication administration creates challenges for families and clinical staff. METHODS A retrospective chart review was completed on 11 patients who received this treatment with various combinations of oral medications (thalidomide, etoposide, cyclophosphamide, celecoxib, and fenofibrate), intravenous (IV) medication (bevacizumab), and intraventricular chemotherapy (cytarabine, etoposide, and topotecan). We implemented successful nursing interventions, family education, variable scheduling options, dosage formulation selections, and innovative oral and intraventricular administration techniques. RESULTS Patients were able to successfully receive therapy for an average of 14 months and no patient came off for toxicity. Treatment was generally well-tolerated, with most toxicities being hematologic or gastrointestinal in nature. CONCLUSION Education, innovative dosing schedules, recognition of potential side effects, and medication administration allow for successful administration of this complex therapy.

Retrospective National “Real Life” Experience of the SFCE with the Metronomic MEMMAT and MEMMAT-like Protocol

Relapses in pediatric high-risk brain tumors remain unmet medical needs. Over the last 15 years, metronomic chemotherapy has gradually emerged as an alternative therapeutic approach. This is a national retrospective study of patients with relapsing pediatric brain tumors treated according to the MEMMAT or MEMMAT-like regimen from 2010 to 2022. Treatment consisted of daily oral thalidomide, fenofibrate, and celecoxib, and alternating 21-day cycles of metronomic etoposide and cyclophosphamide associated with bevacizumab and intraventricular chemotherapy. Forty-one patients were included. The most frequent malignancies were medulloblastoma (22) and ATRT (8). Overall, the best responses were CR in eight patients (20%), PR in three patients (7%), and SD in three patients (7%), for a clinical benefit rate of 34%. The median overall survival was 26 months (IC95% = 12.4-42.7), and median EFS was 9.7 months (IC95% = 6.0-18.6). The most frequent grade ¾ toxicities were hematological. Dose had to be adjusted in 27% of the cases. There was no statistical difference in outcome between full or modified MEMMAT. The best setting seems to be when MEMMAT is used as a maintenance and at first relapse. The metronomic MEMMAT combination can lead to sustained control of relapsed high-risk pediatric brain tumors.

How I treat recurrent pediatric high-grade glioma (pHGG): a Europe-wide survey study

PurposeAs there is no standard of care treatment for recurrent/progressing pediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies.MethodsIn a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG).Results139 clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8–92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55–77% recommended (re-)irradiation, preferably local radiotherapy > 20 Gy. Most respondents would participate in clinical trials and use targeted therapy (79–99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64–88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31–72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20–69% proposed immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6–18%), HDAC inhibitors (4–15%), tumor-treating fields (1–26%), and intraventricular chemotherapy (4–24%).ConclusionIn each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressing HGG.

QLTI-17. PROPHYLACTIC VANCOMYCIN REDUCES OMMAYA RESERVOIR-ASSOCIATED BACTERIAL MENINGITIS: A 12-MONTH PROSPECTIVE STUDY

Abstract INTRODUCTION Intraventricular chemotherapy administered through an Ommaya reservoir (OR) constitutes the mainstay of therapy for adults with leptomeningeal metastases from solid and hematologic malignancies. Unfortunately, OR-associated bacterial meningitis remains a relatively frequent, costly, often morbid, and occasionally fatal complication, limiting the benefit of this approach. We investigated the potential efficacy, cost savings, and toxicity of intraventricular vancomycin co-administered with intraventricular chemotherapy. METHODS Detailed demographic, treatment, and outcome data were collected prospectively between 5/1/21 and 4/30/22 for 63 consecutive patients at our institution who underwent OR placement and subsequent intraventricular chemotherapy, co-administered with 10 mg of intraventricular vancomycin at each treatment. Reservoir-associated bacterial meningitis was defined as 2 consecutive positive cultures from the cerebrospinal fluid of the same organism or 1 positive culture in the presence of any other clinical or laboratory evidence of infection, or signs of infection at the surgical site. RESULTS The infection rate was 0% [95% CI 0-6.75%] among the 63 patients and 0% [0-0.76%] in the 501 consecutive treatments administered over the 12-month study period compared to 10.25% [7.39- 14.0%] in 322 patients and 1.71% [1.22-2.39%] in 1932 treatments over the preceding 5 years. The absolute risk reduction was 10.3% [3.83 - 14.04], p = 0.0049. The number needed to treat was 10 [7-26]. Cost per vancomycin dose was $10.00 ($5,010 over 12 months). The cost of non-surgical treatment of one OR-associated infection is $88,337.70, which translates into a $618,363.90 savings for the estimated 7 patients over 12 months spared an OR-associated infection. Savings were even further increased if OR removal and subsequent replacement was required. The only other covariate associated with (increased) infection risk on multivariable analysis was treatment number. No treatment-associated toxicity was observed. CONCLUSION Prophylactic intraventricular vancomycin eliminated OR-associated infection in patients receiving intraventricular chemotherapy. Dramatic cost savings were achieved without added toxicity.

NCMP-10. NEURO-OPHTHALMOLOGICAL FINDINGS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA - A RETROSPECTIVE ANALYSIS

Abstract BACKGROUND Medulloblastoma represents the most common malignant pediatric brain tumor. Ophthalmic complications are possible sequelae. METHODS Pediatric medulloblastoma (MB) patients treated at the Medical University of Vienna from January 2012 to August 2021 were analyzed and their last ophthalmic assessment was reviewed. RESULTS Fifty-six MB patients could be included (71.4% non-WNT/non-SHH, 16.1% SHH-activated, 8.9% WNT-activated, 3.6% non-specified). Mean age at diagnosis was 7.2 years (range 0-19). Median follow-up to last ophthalmological assessment was 19.7 months (range 0.1-93.2). Thirty-four children underwent tumor resection at our hospital, their tumor localizations were: vermis (55.9%), floor of the 4th ventricle (26.5%), cerebellar hemispheres (11.8%), lateral recess (5.9%). Symptoms at presentation were evaluable for 51 children: 92.2% had symptoms of elevated intracranial pressure, 76.5% ataxia and 21.6% visual disturbances. Postoperative posterior fossa syndrome was observed in 11.1% of 54 children. 98.2% had chemotherapy as part of their initial treatment and all children older than four years (85.7%) received postoperative irradiation of the posterior fossa. In 13 (23.2%) intraventricular chemotherapy was applied. At the last follow-up 21 patients experienced relapse after primary treatment. At the final assessment, frequent neuro-ophthalmological abnormalities included: oculomotor disturbance (75%), esotropia (35.7%) including abducens palsy (12.5%), other cranial nerve palsies (21.4%), horizontal gaze-evoked nystagmus (51.8%), spontaneous nystagmus (16.1%), ocular tilt reaction (21.4%), and optic disc abnormalities (14.3%). Good visual acuity (≥20/25) was maintained in 62.5% patients. Visual field and optical coherence tomography was successfully performed in 75% and 66.1% of patients, respectively. Optic pathway lesions were detected in 4 patients (7.1%), including two cases with occipital metastases, one with optic nerve metastasis and one with leptomeningeal carcinomatosis. Orthoptic treatment with prisms and strabismus surgery was required in 14.3% and 7.7% of children, respectively. CONCLUSION Children with MB frequently suffer from neuro-ophthalmological late-effects. Regular monitoring is warranted to initiate appropriate management.

LOCL-11 EGFR-MUTATED NON-SMALL CELL LUNG CANCER (NSCLC) LEPTOMENINGEAL DISEASE (LMD) IN A LARGE STEREOTACTIC RADIOSURGERY PATIENT COHORT: INCIDENCE AND OUTCOME

Abstract AIM Patients with EGFR-mutated NSCLC brain metastases (BM) treated with targeted agents +/- radiosurgery (SRS) have increasing life expectancies. Systemic treatment may become less effective in preventing CNS progression as survival is prolonged. We sought to identify subsequent LMD in patients with EGFR-mutated NSCLC treated initially with SRS for BM and describe the associated features, treatment, and outcome. METHODS Review of our prospective Gamma Knife registry identified 177 patients with EGFR-mutated NSCLC between 2005 and 2021 treated with SRS. The EMR was queried for development of LMD, and type of LMD was recorded (focal/nodular or diffuse). RESULTS 38 (21%) of the 177 patients developed LMD at a median of 10 months (range 1-25 IQR) following SRS. 27 (71%) of these were on tyrosine kinase inhibitors (TKI) at time of LMD diagnosis. Median overall survival (OS) from initial SRS for the entire cohort was 21 months (18-27 95%CI). Median OS after LMD diagnosis was 5 months (2-32 95%CI). LMD was diagnosed radiographically in 35 patients (92%); 20 patients had diffuse, 15 had focal/nodular, and 3 had positive CSF cytology. 26 (68%) had systemic progression synchronously with LMD. 33 (87%) had treatment for LMD including 19 with whole brain radiation therapy, 16 with the addition of or increased dosing of TKI, 6 with SRS for nodular disease, and 9 with intraventricular chemotherapy. The one- and two-year survival rates following the diagnosis of LMD was 21% and 3%, respectively. CONCLUSION LMD developed in a substantial subset of our patients, and despite the use of a variety of salvage therapies, survival was poor. Investigation to identify factors correlating with the development of LMD and those related to outcome are ongoing. The development of LMD on TKI in several of our patients supports efforts to pursue development of therapeutic agents with long-lasting CNS efficacy.

Sellar Atypical Teratoid/Rhabdoid Tumors (AT/RT): A Systematic Review and Case Illustration.

Introduction: Atypical Teratoid/Rhabdoid tumors are rare, highly malignant tumors in adults, with a median survival of 20 months. We report a case of a sellar atypical teratoid/rhabdoid tumor in a 70-year-old female treated with intraventricular chemotherapy, followed by a systematic review of the current management of sellar AT/RTs.Methods: A comprehensive systematic literature search was conducted on Web of Science, Scopus, and PubMed Central using the key terms “sellar” and “atypical teratoid/rhabdoid tumors”, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data, including patient demographics, histology, treatments, and overall survival were extracted and analyzed. Kaplan-Meier survival curves and log-rank analysis were used to compare survival outcomes between different treatment regimens.Results: Our literature search disclosed 123 publications. After prespecified exclusions, 41 patients with sellar AT/RT from 30 manuscripts were identified, and 38 were included in the final analysis. Including our patient, the median age was 44 (range: 20-70) with a substantial female predominance (94.7%). Collectively, patients who received combined chemoradiation therapy had a significantly increased overall survival compared to those who received single modality or no adjuvant therapies (median OS 27 vs. 1.25 months; p=0.0052).Conclusion: Atypical teratoid/rhabdoid tumor in the sellar region carries a poor prognosis. Adjuvant chemotherapy and radiation therapy were associated with significantly increased overall survival. Early consideration of neuro-oncology and radiation-oncology referral and management is likely beneficial in this patient population. Intrathecal chemotherapy is a treatment modality that requires further exploration given the limited options and current dismal prognosis of adult sellar AT/RT.

How do we approach the management of medulloblastoma in young children?

Therapeutic strategies avoiding craniospinal irradiation were developed for young children with medulloblastoma to improve survival while protecting the neurocognitive outcomes of these vulnerable patients. These strategies most commonly rely on high-dose chemotherapy with stem cell rescue or conventional chemotherapy combined with intraventricular chemotherapy or conventional chemotherapy with adjuvant focal irradiation. Over the past decade, our growing understanding of the molecular landscape of medulloblastoma has transformed how we risk stratify and allocate treatment in this young age group. We present the results of the most recent approaches and clinical trials for medulloblastoma of early childhood, according to the different molecular subgroups. Overall, young children with sonic hedgehog medulloblastoma treated with intensive adjuvant chemotherapy achieve excellent survival and can safely be spared from radiotherapy. For patients with group 3 and 4 medulloblastomas, the interplay between molecular alterations and treatment intensity still needs to be further delineated. While recent clinical trials point toward more encouraging survival figure for a sizeable number of them, patients identified with very high-risk feature desperately needs innovative therapies.

HGG-29. How I treat recurrent pediatric high-grade glioma (HGG): A Europe-wide survey study.

PURPOSE: Prognosis of pediatric high-grade gliomas (pedHGG) is dismal, and there is no standard of care treatment in case of recurrence/progression. We aimed to gain an overview of different treatment strategies in the setting of recurrent/progressing pedHGG. METHODS: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on different therapeutic options in four real-world case scenarios (children/adolescents with recurrent/progressing HGG). RESULTS: One hundred and thirty-nine clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further active (multimodal) oncological treatment in three out of four cases and chose palliative care with pure symptom control measures only in one case (gliomatosis cerebri and marked symptoms). Depending on the case, 8-92% of experts would initiate a re-resection (maximal safe resection in case of localized hemispheric pedHGG), combined with molecular diagnostics, and 55-77% recommended (re-)irradiation, preferably local radiotherapy >20 Gy (or craniospinal irradiation in one case with disseminated spinal HGG, 65%). Throughout all case scenarios, most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitors, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% advocated immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumor-treating fields (1-26%), and intraventricular chemotherapy (4-24%). CONCLUSIONS: In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a standard (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressive HGG.

Quantifying intraventricular drug delivery utilizing programmable ventriculoperitoneal shunts as the intraventricular access device.

Programmable ventriculoperitoneal shunts (pVP shunts) are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of drug concentrations in the thecal space with minimization in the peritoneum. This report assesses the success of the pVP shunt as an access device for intraventricular therapies. Quantifying intrathecal drug delivery using scintigraphy by pVP shunt model has not been previously reported. We performed a single-institution, retrospective analysis on patients with CNS tumors and pVP shunts from 2003 to 2020, noting shunt model. pVP flow was evaluated for consideration of compartmental radioimmunotherapy (cRIT) using In-111-DTPA scintigraphy. Scintigraphy studies at 2-4h and at 24h quantified ventricular-thecal and peritoneal drug activity. Twenty-two CSF flow studies were administered to 15 patients (N = 15) with diagnoses including medulloblastoma, metastatic neuroblastoma, pineoblastoma, and choroid plexus carcinoma. Six different types of pVP models were noted. 100% of the studies demonstrated ventriculo-thecal drug activity. 27% (6 of 22) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 22) of the studies had minimal relative peritoneal uptake (< 12%). 27% (6 of 22) of the studies demonstrated moderate relative peritoneal uptake (12-37%). No studies demonstrated peritoneal uptake above 37%. All patients had successful drug delivery of In-111-DTPA to the ventriculo-thecal space. 73% of the patients had minimal relative (< 12%) peritoneal drug uptake. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies assesses drug distribution of In-111-DTPA, informing CSF flow for delivery of intraventricular therapies.

Lumboperitoneal Shunt Combined With Ommaya Reservoir Enables Continued Intraventricular Chemotherapy for Leptomeningeal Metastasis With Increased Intracranial Pressure.

Intra-cerebrospinal fluid (CSF) chemotherapy for leptomeningeal metastasis (LM) can be delivered intraventricularly via an Ommaya reservoir. However, hydrocephalus associated with LM can interfere with chemotherapeutic drug distribution, and ventriculoperitoneal shunts can prevent drug distribution to the extra-ventricular CSF space. This study examined the feasibility of combining a lumboperitoneal (LP) shunt with an Ommaya reservoir to both control intracranial pressure and allow for intraventricular chemotherapy. We identified 16 patients with LM who received both an Ommaya reservoir and an LP shunt, either concurrently or sequentially, and subsequently received intraventricular chemotherapy. The feasibility of this combination for intraventricular chemotherapy was evaluated by assessing 1) the distribution of intraventricularly injected drugs in CSF samples collected 0, 6, and 12 h post-injection and 2) adverse events associated with the procedure and drug administration. Patients received a median of seven rounds (range 1-37) of intraventricular chemotherapy during a median follow-up period of 5.2 months after LP shunt insertion. Pharmacokinetic data were obtained from six patients. Baseline methotrexate (MTX) levels from Ommaya reservoirs varied from 339.9 µM to 1,523.5 µM. CSF sampled from LP shunt reservoirs revealed an elimination half-life (t1/2) of 2.63 h, and the mean ratio of MTX concentration at 12 h to that at baseline was 0.05±0.05, ensuring drug distribution from the ventricle to the spinal canal. Nine patients (56%) underwent revision surgery due to catheter migration, malfunction, or infection. Among these patients, CSF infections attributable to intraventricular chemotherapy (n=3) occurred, but no infections occurred in later cases after we began to employ a complete aseptic technique. LP shunt combined with Ommaya reservoir insertion is a feasible option for achieving both intracranial pressure control and the continuation of intraventricular chemotherapy in patients with LM.

LMD-01. Quantifying intrathecal drug delivery utilizing programmable ventriculoperitoneal shunts

BackgroundProgrammable ventriculoperitoneal shunts (pVP shunts) are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of thecal space drug concentrations with minimization in the peritoneum. Drug delivery quantification using several types of pVP shunts has not been reported.MethodsWe performed a retrospective analysis on patients with CNS tumors and pVP shunts at Memorial Sloan Kettering Cancer Center from 2003–2020, noting shunt model. CSF flow through the pVP shunt was evaluated using In-111-DTPA scintigraphy at approximately 4 and 24 hours after injection. pVP shunts were calibrated pre-injection to minimize peritoneal flow and re-calibrated to baseline setting 4–5 hours following injection. Scintigraphy studies quantified ventricular-thecal and peritoneal drug activity at these 2 time points.ResultsTwenty-one CSF flow studies were administered to 15 patients, ages 1–27 years. Diagnoses included medulloblastoma (N=10), metastatic neuroblastoma (N=3), pineoblastoma (N=1), and choroid plexus carcinoma (N=1). Models of pVP shunts included Aesculap Miethke proGAV (N=3), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 5), and Sophysa Polaris (N= 1). All 21 studies (100%) demonstrated ventriculo-thecal drug activity. 29% (6 of 21) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 21) of the studies had minimal peritoneal uptake (<12%), and 24% (5 of 21) demonstrated moderate peritoneal uptake (12–37%). Models of pVP shunts measuring minimal to no peritoneal uptake included: Aesculap Miethke proGAV (N=2), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 3), and Sophysa Polaris (N= 1).ConclusionspVP shunts successfully deliver drugs to the ventriculo-thecal space with 80% of studies having minimal (<12%) peritoneal drug activity. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies reliably assess drug distribution.

Cerebrospinal Fluid Profiles and Their Changes after Intraventricular Chemotherapy as Prognostic or Predictive Markers for Patients with Leptomeningeal Carcinomatosis.

ObjectiveHere, we evaluated whether cerebrospinal fluid (CSF) profiles and their changes after intraventricular chemotherapy for leptomeningeal carcinomatosis (LMC) could predict the treatment response or be prognostic for patient overall survival (OS) along with clinical factors. MethodsPaired 1) pretreatment lumbar, 2) pretreatment ventricular, and 3) posttreatment ventricular samples and their CSF profiles were collected retrospectively from 148 LMC patients who received Ommaya reservoir installation and intraventricular chemotherapy. CSF profile changes were assessed by calculating the differences between posttreatment and pretreatment samples from the same ventricular compartment. CSF cell counts were further differentiated into total and other based on clinical laboratory reports. ResultsFor the treatment response, a decreased CSF ‘total’ cell count tended to be associated with a ‘controlled’ increase in intracranial pressure (ICP) (p=0.059), but other profile changes were not associated with either the control of increased ICP or the cytology response. Among the pretreatment CSF profiles, lumbar protein level and ventricular cell count were significantly correlated with OS in univariable analysis, but they were not significant in multi-variable analysis. Among CSF profile changes, a decrease in ‘other’ cell count showed worse OS than ‘no change’ or increased groups (p=0.001). The cytological response was significant for OS, but the hazard ratio of partial remission was paradoxically higher than that of ‘no response’. ConclusionA decrease in other cell count of CSF after intraventricular chemotherapy was associated with poor OS in LMC patients. We suggest that more specific CSF biomarkers of cancer cell origin are needed.

IMMU-15. QUANTIFYING INTRATHECAL DRUG DELIVERY UTILIZING PROGRAMMABLE VENTRICULOPERITONEAL SHUNTS

BackgroundProgrammable ventriculoperitoneal (pVP) shunts are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of thecal space drug concentrations with minimization in the peritoneum. Drug delivery quantification using several types of pVP shunts has not been reported. MethodsWe performed a retrospective analysis on patients with CNS tumors and pVP shunts at Memorial Sloan Kettering Cancer Center from 2003–2020, noting shunt model. CSF flow through the pVP shunt was evaluated using In-111-DTPA scintigraphy at approximately 4 hours and 24 hours after injection. pVP shunts were calibrated pre-injection to minimize peritoneal flow and re-calibrated to baseline setting 4–5 hours following injection. Scintigraphy studies quantified ventricular-thecal and peritoneal drug activity at these 2 time points. ResultsTwenty-one CSF flow studies were administered to 15 patients, ages 1–27 years. Diagnoses included medulloblastoma (N=10), metastatic neuroblastoma (N=3), pineoblastoma (N=1), and choroid plexus carcinoma (N=1). pVP shunt models included Aesculap Miethke proGAV (N=3), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 5), and Sophysa Polaris (N= 1). All 21 studies (100%) demonstrated ventriculo-thecal drug activity. 29% (6 of 21) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 21) of the studies had minimal peritoneal uptake (<12%), and 24% (5 of 21) demonstrated moderate peritoneal uptake (12–37%). pVP shunt models measuring minimal to no peritoneal uptake included: Aesculap Miethke proGAV (N=2), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 3), and Sophysa Polaris (N= 1). ConclusionsSuccessful drug delivery to the ventriculo-thecal space can be accomplished using pVP shunts: 80% of studies have minimal (<12%) peritoneal drug activity. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies reliably assess drug distribution.

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis.

Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of NRAS (n = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type.

How I do it: ultrasound-guided placement of ommaya reservoir in a patient with small ventricles and cavum septum pellucidum.

Intraventricular chemotherapy via Ommaya reservoir is an important part of the treatment in patients with malignant central nervous system tumors. In these patients, catheter placement can be challenging due to the normal-sized ventricles. Intraoperative ultrasound guidance was used for Ommaya reservoir placement in a 56-year-old patient with multiple intracranial and leptomeningeal metastases who had cavum septum pellucidum et vergae malformation. The catheter was successfully placed into the frontal horn of the lateral ventricle outside the cavum. Intraoperative ultrasound is a suitable image guidance system in patients with slit-like or normal-sized ventricles. It can also be used in patients with ventricular malformations.