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Real life experience of complete remission with modified MEMMAT regimen with LACE induction followed by ASCT as consolidation in Recurrent Medulloblastoma -A case report
*Corresponding author: Mukul Arvind Gharote, Department of Medical Oncology, Mukta Cancer Clinic, Nashik - 422009, Maharashtra, India. mukul.gharote@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Gharote MA, Kalantri SA, Wasekar NP, Deogaonkar AN. Real life experience of complete remission with modified MEMMAT regimen with LACE induction followed by ASCT as consolidation in Recurrent Medulloblastoma - A case report. Int J Mol Immuno Oncol. 2025;10:76-80. doi: 10.25259/IJMIO_31_2024
Abstract
Medulloblastoma is a central nervous system tumor, it often recurs, and recurrence, if disseminated, is usually treated with high-dose chemotherapy of cyclophosphamide and etoposide. This therapy is replete with adverse effects, and compliance becomes a significant issue. Metronomic therapy is the safest way to treat malignancies in a very gentle manner. Compliance is very high, and response can be durable and deep. We present a real-life experience of using modified metronomic and targeted antiangiogenesis therapy for children with recurrent/progressive medulloblastoma, a regimen used in a case of a disseminated medulloblastoma patient.
Keywords
Disseminated medulloblastoma
LACE
Medulloblastoma
MEMMAT
Modified MEMMAT
INTRODUCTION
Recurrent medulloblastoma (rMB) with disseminated metastasis is usually treated with high-dose cyclophosphamide with etoposide, and various other regimens containing high-dose cyclophosphamide with etoposide and carboplatin/cisplatin, whereas some regimens use irinotecan along with bevacizumab with or without temozolomide.
In our case, because the bone marrow was involved, the patient had significant neutropenia and thrombocytopenia, making it difficult to administer these regimens. The patient would have been at risk of significant blood-component depletion and could not afford the associated financial burden. After discussion with the patient, a relatively less toxic regimen—the Medulloblastoma European Multitarget Metronomic Anti-angiogenic Trial (MEMMAT) protocol—was selected.
CASE REPORT
We present a case report of a 12-year-old boy suffering from rMB stage IV. His previous history is as follows: he is a diagnosed case of medulloblastoma of the cerebellar vermis-ventriculo-peritoneal shunt with reservoir insertion along with posterior fossa-craniotomy done in 2018–2019. On January 14, 2019, his cerebrospinal fluid (CSF) examination was suggestive of infiltration by medulloblastoma cells. He was given Craniospinal Irradiation (35 Gy/21#) with Tumour Boost (19.8 Gy/18#) along with injectable carboplatin concurrently in 2019. No further adjuvant treatment was given. He had a 4 years of disease-free survival. In February 2023, he presented with knee pain and backache. A positron emission tomography (PET) scan was suggestive of increased activity in the axial skeleton, with the entire bone marrow involved. He underwent bone marrow aspiration and biopsy, which was suggestive of non-hematopoietic cells in clusters, and immunohistochemistry test was positive for synaptophysin, suggestive of medulloblastoma recurrence.
After proving recurrence, he was treated with the modified MEMMAT regimen and he achieved near complete regimen after 6 cycles of MEMMAT regimen. This was followed by autologous stem cell transplantation (ASCT) as consolidation. He received 6 months of maintenance chemotherapy.
The Modified MEMMAT regimen comprises injection of bevacizumab 10 mg/kg every 14 days, tabet cyclophosphamide 50 mg/m2 once a day for 21 days alternating with capsule Etoposide 50 mg/m2, tabet Fenofibrate 90 mg/m2 every day for 21 days, tabet Celecoxib 200 mg BD every day for 21 days, and tabet Thalidomide 3 mg/kg every day for 21 days. Six cycles of MEMMAT were given every 21 days, and follow-up PET scan with bone marrow aspiration was done. Disease was in remission in both the marrow sample as well as in PET scan. The patient underwent autologous bone marrow transplantation details of which are as follows.
Peripheral blood stem cells were harvested using granulocyte colony-stimulating factors and injection plerixafor.
Induction regimen lomustine, cytarabine, cyclophosphamide, and etoposide (LACE), which comprises of injection cyclophosphamide 1800 mg/m2 day 2,3,4 was given, with fungal prophylaxis of oral posaconazole was given, injectable cytosine arabinoside 2000 mg/m2 day 5–6 with prednisolone eye drop as prophylaxis against conjunctivitis/scleritis, cap lomustine 200 mg day 7 injectable etoposide 1000 mg/m2 day 7. The patient was transfused peripheral blood stem cells, CD 4 count of 4.97×106/kg. Engraftment occurred on day 12, on granulocyte colony-stimulating factor support from day 7 to 16.
The patient was given 6-month post-ASCT maintenance with the MEMMAT regimen and is in remission.
As shown in Figure 1, his day 1 PET scan showing disease activity in the bones as well as bone marrow, whereas the figure on the left side shows partial remission to 6 cycles of MEMMAT.
- Positron emission tomography scan comparison before (right) and after (left) metronomic and targeted antiangiogenesis therapy regimen.
DISCUSSION
rMB with disseminated metastases is a challenge to be treated especially in cases where bone marrow is infiltrated by medulloblastoma cells. Often the regimen used can be toxic and lead to febrile neutropenia.
MEMMAT regimen is relatively less toxic and tolerable. Modified MEMMAT regimen comprises as mentioned in Table 1
| Drug | Dose | Day |
|---|---|---|
| Bevacizumab | 10 mg/kg | 1’14 |
| Etoposide/Endoxan | 50 mg/m2 | 1–21 |
| Fenofibrate | 90 mg/m2 | 1–21 |
| Celecoxib | 200 mg BD | 1–21 |
| Thalidomide | 3 mg/kg | 1–21 |
Bevacizumab at dose 10 mg/kg every 14 days, and tab Cyclophosphamide alternating with etoposide at dose 50 mg/m2. Fenofibrate 90mg/m2 – was rounded about to nearest dose of 160 mg/200 mg of fenofibrate, celecoxib 200 mg BD –and Thalidomide at dose 3 mg/kg every 14 days.
Original MEMMAT has 3 components, (1) oral tablets 5 drug regimen of thalidomide, fenofibrate and celecoxib with alternate etoposide and cyclophosphamide, (2) intravenous bevacizumab 10 mg/kg every 14 days, and (3) intraventricular through Ommaya reservoir, alternating every 2 weeks, etoposide 0.5 mg for 5 days, liposomal cytarabine 25 mg–50 mg (as per age). As shown in Figure 2, bevacizumab is given every 14 days [Figure 3].
- Original MEMMAT based therapy.
- Treatment schema of metronomic and targeted antiangiogenesis therapy regimen.
MEMMAT for children with recurrent/progressive medulloblastoma
Earlier studies scrutinizing the use of bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide alternating with cyclophosphamide, and intrathecal therapy (alternating liposomal cytarabine and etoposide) in relapsed brain tumors suggested encouraging results in patients with recurrent medulloblastoma, i.e., rMB (n = 7).[1] Toxicities reported were neutropenia, infection, and peripheral neuropathy secondary to thalidomide, hypothyroidism, proteinuria, and hematuria. Papilledema and raised intracranial pressure were noted following intraventricular liposomal cytarabine in 2 patients.
In the light of these encouraging findings, a phase II study, MEMMAT (NCT01356290), was opened.[2] An interim report of the first 29 patients recruited to MEMMAT between 2006 and 2016 has recently been presented, albeit the trial is still recruiting.[1] All 29 patients had rMB (19 first relapse and 10 multiple relapses) with a median age of 10 years (range 1–27 years). Currently, eight out of 29(27 %) patients are alive with 6/8 in continuous complete remission. The treatment was reported to be well tolerated, although five patients died of other causes such as secondary leukemia and sepsis. Event-free survival were 33% and 28% at 5 and 10 years, overall survival was 44% and 39% at 5 and 10 years, respectively. We await the results of the MEMMAT trial which was completed in 2023.[1]
Modified MEMMAT
It is not uncommon for individual clinicians to adapt the MEMMAT regimen to meet the needs of their patients, minimise toxicity, or conform to regulatory requirements where some agents are not readily available. A common adaptation includes the administration of alternating 3 weekly cycles of etoposide and cyclophosphamide/trofosfamide alone or 1 weekly cycles of temozolomide and topotecan (data HIT-REZ-2005 study and HIT-REZ-Registry cohort).[3] Pre-clinical and clinical evidence for these approaches are not available, but anecdotally, they are typically well tolerated and may prolong survival.
We modified the MEMMAT in the form of 14-day cycle according to bevacizumab administration, dose of endoxan and etoposide was fixed to 50 mg. Our justification for 50 mg endoxan was its use as metronomic oral chemotherapy at flat dose of 50 mg in recurrent ovarian carcinoma.[4]
We did not give intracranial administration through Ommaya reservoir; our rationale was due to pre-irradiation, the blood brain barrier was rendered ineffective; hence, there was no role of specific intracranial chemotherapy.[5]
Besides, we planned for LACE[6] as induction chemotherapy to take care of the intracranial component of medulloblastoma. LACE has lomustine, cytosine arabinoside, cyclophosphamide, and etoposide as chemotherapy. LACE is very effective as induction chemotherapy in refractory lymphoma.[6] Lomustine has an action against medulloblastoma cells[7] and etoposide is also a drug used in the medulloblastoma regimen. Even cytosine arabinoside (ARA-C) has a role in medulloblastoma treatment as a part of proteasome inhibitors (bortezomib) (PAE) regimen.[8] Cyclophosphamide although at a higher dose has shown its role in medulloblastoma, it has shown action in cell lines of medulloblastoma.[9] Thus, LACE induction was not only the best induction regimen but may also be one of the best chemotherapy agents against medulloblastoma as well.
MEMMAT and its modified version have shown significant results in phase II non-randomized multi-center trial conducted on 40 patients of recurrent and/or refractory medulloblastoma who were previously irradiated.[10] MEMMAT offers an extremely well-tolerated oral anti-angiogenic option and we need a larger study in this regard.
CONCLUSION
Thus, we suggest a modified MEMMAT regimen along with LACE induction chemotherapy to be one of the treatments for disseminated medulloblastoma in general and bone marrow seeding of medulloblastoma in particular.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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