Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor. Authors; Authors and affiliations. Mary Ann ...
Springer 2005
Journal of Neuro-Oncology (2005) 72: 77–84
Clinical Study
Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor Mary Ann Zimmerman1,2, Liliana C. Goumnerova3, Mark Proctor3, R. Michael Scott3, Karen Marcus4, Scott L. Pomeroy5, Christopher D. Turner1,2, Susan N. Chi1,2, Christine Chordas1,2 and Mark W. Kieran1,2 1 Department of Pediatric Oncology, Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Boston; 2Division of Hematology/Oncology; 3Department of Neurosurgery; 4Department of Radiation Oncology, Children’s Hospital; 5 Department of Neurology, Children’s Hospital, Boston, MA, USA
Key words: atypical teratoid/rhabdoid tumor (AT/RT), brain tumor, pediatric, rhabdoid, treatment Summary Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant lesions of childhood that carry a very poor prognosis. AT/RT can occur in the central nervous system (CNS AT/RT) and disease in this location carries an even worse prognosis with a median survival of 7 months. In spite of multiple treatment regimens consisting of maximal surgical resection (including second look surgery), radiation therapy (focal and craniospinal), and multiagent intravenous, oral and intrathecal chemotherapy, with or without high-dose therapy and stem cell rescue, only seven long-term survivors of CNS AT/RT have been reported, all in patients with newly diagnosed disease. For this reason, many centers now direct such patients, particularly those under 5 years of age, or those with recurrent disease, towards comfort care rather than attempt curative therapy. We now report on four children, two with newly diagnosed CNS AT/RT and two with progressive disease after multi-agent chemotherapy who are long term survivors (median follow-up of 37 months) using a combination of surgery, radiation therapy, and intensive chemotherapy. The chemotherapy component was modified from the Intergroup Rhabdomyosarcoma Study Group (IRS III) parameningeal protocol as three of the seven reported survivors in the literature were treated using this type of therapy. Our four patients, when added to the three reported survivors in the literature using this approach, suggest that patients provided this aggressive therapy can significantly alter the course of their disease. More importantly, we report on the first two survivors after relapse with multi-agent intravenous and intrathecal chemotherapy treated with this modified regimen.
Introduction Central nervous system atypical teratoid/rhabdoid tumors (CNS AT/RT) are highly malignant neoplasms primarily affecting young children [1]. First described in 1985 [2], there have been approximately 200 cases reported since its formal description [3] although the actual number of cases may have been significantly underestimated due to historical grouping with other malignant high-grade embryonal CNS lesions such as medulloblastoma and primitive neuroectodermal tumor (PNET) [4,5]. Patients have typically undergone attempted radical surgical resection followed by either local field or craniospinal irradiation and/or chemotherapy regimens used in the treatment of other seeding, high-grade CNS malignancies. In spite of this, most patients have suffered rapid disease recurrence and death due to progression [6,7]. A review of the literature regarding outcomes for patients with newly diagnosed CNS AT/RT is dismal with the median time to death reported between 6 and 11 months [1,4]. Weinblatt and Kochen [8] published a single case report of the first sustained remission of CNS AT/RT after surgery, radiation therapy and multi-agent che-
motherapy using the Intergroup Rhabdomyosarcoma III (IRS III) designed for parameningeal rhabdomyosarcoma (Regimen 36). Similarly, Olson et al. [9] reported their experience in which three patients with newly diagnosed CNS AT/RT achieved prolonged remission following surgery, radiation and chemotherapy, again based on the IRS III Regimen 36, two of whom are long-term survivors. In the intervening decade, a number of patients with CNS AT/RT have been treated with further modifications to the IRS III-based regimen, although no successful cases have been reported. For this reason, we chose to return to the original protocol and treat four sequential patients with therapy (referred to as DFCI/IRS III) that more closely matched those in which a positive outcome had been obtained. Our patients have included two cases of newly diagnosed and most strikingly, two cases of recurrent CNS AT/RT, both of whom had received prior maximal surgery, multi-agent intravenous and intrathecal chemotherapy. These four patients remain alive and well without evidence of disease at a median of 3 years 1 month from diagnosis. The details of these cases are presented for review and compared with those in the literature.
78 addition of dexrozoxane might impede the activity of doxorubicin, the known significant cardiotoxicity of this drug at doses exceeding 360 mg/m2 mandated this modification. The diagnosis of CNS AT/RT was confirmed by the Department of Neuropathology at Children’s Hospital Boston for all patients and independently verified by at least one outside institutional review. The pathological findings of the four cases are presented in Table 3 and include the presence of rhabdoid cells in all patients. Because of the unusual EMA and desmin pattern in patient 4, the presence of the INI-1 mutation was confirmed.
Methods The outcome of four consecutive children treated for central nervous system AT/RT between December 1999 and April 2002 at the Dana-Farber Cancer Institute are reported. The DFCI/IRS III based therapy and doses utilized for the patients in this report are outlined in Table 1 (newly diagnosed CNS AT/RT) and Table 2 (recurrent CNS AT/RT). The decision to maintain therapy as closely to the original two reports [8,9] of the IRS III Regimen 36 was made as unpublished observations from groups that had used modified versions of this approach did not achieve comparable outcomes. Of note, a few potentially significant modifications to the therapy were made. For children less than three, craniospinal irradiation therapy was omitted and substituted with focal stereotactic radiation therapy. Second, DTIC was substituted with Temozolomide, both of which are converted to MTIC but for which dosing and administration are easier with Temozolomide. Finally, use of the cardio-protectant dexrozoxane in patients receiving doses of doxorubicin in excess of 360 mg/m2 was included. While it was considered possible that the
Patients Patient 1 This previously healthy 2 ½ year old male presented acutely to the Emergency Room after a brief history of progressive headache and lethargy. CT/MRI imaging revealed a large right fronto/temporal lobe enhancing
Table 1. DFCI/IRS III based therapy for newly diagnosed CNS AT/RT (Patients 1 and 4) Week number 1
2
3
4
5
6
7
8
9
10
11
12
13
16
19
23
V P D C
V
V
V P D
V
V
V P
V
V
V P
V
V
V
V
T A*
T A*
D C
C
C* E
E
C* E
27
30
V D C
V* C A
A I L
I L
Radiation I L
I L
I L
I L
I L
33
V D C
36
V* C A
I L
39
V D* C
42
45
48
51
V*
V* C A
V* C A
V* C A
C A
I L
I L
I L
Agents: Vincristine (V): 2 mg/m2 Day 1. Vincristine (V*): 2 mg/m2 Days 1 and 5. Cisplatin (P): 90 mg/m2 Day 1. Doxorubicin (D): 30 mg/m2/day continuous infusion Days 1 and 2. Doxorubicin (D*): 30 mg/m2/day 15 min infusion. Dexrazoxane (DX): 300 mg/m2 15 min infusion. Cyclophosphamide (C): 300 mg/m2/day continuous infusion Days 1, 2 and 3. Cyclophosphamide (C*): 600 mg/m2 1 h infusion Day 2. Etoposide (E): 100 mg/m2 1 h infusion Days 1, 2 and 3. Actinomycin-D (A): 0.015 mg/kg/day IVP Days 1, 2, 3, 4 and 5. Actinomycin-D (A*): 1.2 mg/m2 IVP (max dose 2.5 mg) OR 0.05 mg/kg in patients less than age 1 year (max dose 2.5 mg) Day 1. Temozolomide (T): 200 mg/m2 if focal radiation OR 150 mg/m2 if CSI po QD Day 1, 2, 3, 4 and 5. Intrathecal (I): Methotrexate 15 mg/m2 (max 15 mg)/Hydrocortisone 30 mg/m2 (max dose 30 mg) Cytarabine 60 mg/m2 (max dose 60 mg). Leucovorin (L): 15 mg/m2 IV/PO administered for one dose 24 h after IT MTX.
Table 2. DFCI/IRS III based therapy for recurrent CNS AT/RT (Patients 2 and 3) Week number 1
2
3
4
8
11
15
18
22
25
29
32
36
39
43
46
50
53
D E
T A
D E
T A
D E
T A
D E
T A
D E
T A
D E
T A
D* E DX
T A
D* E DX
T A
Radiation I I L L
I L
I L
I L
I L
I L
A I L
I L
I L
I L
Agents: Doxorubicin (D): 30 mg/m2/day continuous infusion Days 1 and 2. Doxorubicin (D*): 30 mg/m2/day 15 min infusion. Dexrazoxane (DX): 300 mg/m2 15 min infusion. Etoposide (E): 100 mg/m2 1 h infusion Days 1, 2 and 3. Actinomycin-D (A): 0.015 mg/kg/day IVP Days 1, 2, 3, 4 and 5. Temozolomide (T): 200 mg/m2 po QD Day 1, 2, 3, 4 and 5. Intrathecal (I): Methotrexate 15 mg/m2 (max 15 mg)/Hydrocortisone 30 mg/m2 (max dose 30 mg) Cytarabine 60 mg/m2 (max dose 60 mg). Leucovorin (L): 15 mg/m2 IV/PO administered for one dose 24 h after IT MTX.
79 Table 3. Pathologic and immunohistochemistry criteria for the diagnosis of AT/RT Patient 1 Rhabdoid cells (+) Primitive neuro-ectodermal cells (±) Epithelial cells (±) Mitoses (+) EM for whorled bundles of IF (+) EMA (+) Vimentin (+) SMA (±) GFAP (±) Synaptophysin (±) Desmin ()) Germ cell markers ()) Chromosome 22 deletion (±) INI-1 mutation (±)
+ + + + + + ) ) + ) ) Absent
Patient 2
Patient 3
Patient 4
+ ) ) + + + + + + + ) ) Absent
+ + ) +
+ ) )
+ + + + ) )
) + + + + +
Present
EM – electron microscopy; IF – intermediate filaments; SMA – smooth muscle actin; GFAP – glial fibrillary acidic protein; EMA – epithelial membrane antigen. A blank space mean not tested or reported. The presence or absence of a marker of classic AT/RT is denoted within the brackets in the first column.
mass with resultant hydrocephalus and subfalcine herniation. A sub-total resection was achieved with disease remaining in the right temporal lobe. Pathology was reviewed at Children’s Hospital, Boston and revealed a CNS AT/RT, which was confirmed by a consulting neuropathologist. Metastatic workup including an MRI of the spine and cerebrospinal fluid (CSF) examination was negative. A repeat MRI of the brain obtained immediately prior to initiating therapy revealed progressive nodular enhancement within the resection cavity and right temporal lobe. Therapy was begun based upon DFCI/IRS III. Cycles of chemotherapy were administered every 3–4 weeks as described in Table 1. MRI imaging obtained after two cycles of chemotherapy revealed decreased nodular enhancement surrounding the resection cavity and right temporal lobe (Figure 1). Craniospinal irradiation to a dose of 3060 cGy with a boost to the tumor bed to a total dose of 5040 cGy was then administered concurrently with continuation of DFCI/IRS III based chemotherapy. Following radiation
therapy, a residual nodule remained which was treated with a stereotactic radiosurgical (SRS) boost. MRI imaging following the SRS boost and all subsequent scans continue to be without evidence of residual or recurrent tumor in the brain and spine 4 years from diagnosis. Therapy was well tolerated with the exception of grade IV myelosuppression, vincristine induced peripheral neuropathy, moderate sensorineural hearing loss and significant weight loss/anorexia requiring placement of a gastrostomy tube. Patient 1 continues to be clinically well with stable hearing loss, cognitive delay, hypothyroidism and alopecia. Patient 2 This previously well 14 month old female presented to an outside Emergency Room with new onset seizure activity. An MRI of the brain revealed a large, enhancing mass of the right parietal lobe. A gross total surgical resection was achieved. Pathology demonstrated CNS
Figure 1. Radiographic response of patient # 1: (a) T1 gadolinium contrast enhanced coronal image pre-initiation of DFCI/IRS III based chemotherapy, (b) T1 gadolinium contrast enhanced coronal image 2 months after initiation of chemotherapy.
80 AT/RT at the referring institution and confirmed at Children’s Hospital Boston. Metastatic workup including MRI of the spine, CSF cytology, bone marrow aspirate and biopsy, bone scan, chest and abdomen CT was negative. Therapy was begun on a Pediatric Brain Tumor Consortium trial utilizing multi-agent chemotherapy including mafosfamide, (a pre-activated cyclophosphamide injected intraventricularly and intrathecally twice weekly for 12 doses) and systemic intravenous chemotherapy with vincristine, cisplatin, cyclophosphamide and etoposide. Ten weeks into therapy, this patient once again developed seizure activity. MRI imaging demonstrated disease recurrence with the presence of a 3 cm · 2.8 cm · 3.2 cm enhancing mass in the right parietal lobe. A second operation achieved a gross total resection and the pathology was again CNS AT/RT. A decision to institute DFCI/IRS III based therapy was made with three important modifications. First, because of the young age of this child, stereotactic radiation therapy (5400 cGy) to the tumor bed was used in place of craniospinal irradiation. Second, those agents that had been used prior to the recurrence were eliminated from the DFCI/IRS III based therapy. Third, doxorubicin administration above 360 mg/m2 was changed to a 15 min IV infusion and the cardioprotective agent dexrozoxane 300 mg/m2 was added in order to minimize the risk of cardiotoxicity while continuing to escalate the doxorubicin dose to 480 mg/m2. Therapy was well tolerated with the exception of myelosuppression and a number of episodes of fever and neutropenia. Eight months into therapy, this child developed new onset left hemiparesis and an MRI demonstrated an infarct of the right basal ganglia most likely the result of radiation therapy, although a methotrexate effect could not be excluded [10–12]. A decision was thus made to eliminate methotrexate from the remaining intrathecal chemotherapy. Subsequent MRI imaging has demonstrated stable T2 hyperintensity in the right basal ganglia. Patient 2 continues to be clinically well with a left hemiparesis. MRI imaging has been negative for residual or recurrent tumor, 3 years 5 months from the time of recurrence. Patient 3 This previously well 14 month old female toddler presented to an outside Emergency Room with progressive right sided weakness. An MRI of the brain revealed a large, enhancing mass of the left temporal lobe. A gross total surgical resection was achieved and pathology showed CNS AT/RT as reviewed by the referring institution as well as at Children’s Hospital Boston. Metastatic workup including MRI of the spine, CSF cytology, bone marrow aspirate and biopsy, bone scan, chest and abdomen CT was negative. This patient was enrolled on the Pediatric Brain Tumor Consortium trial as described in Case 2 with the exception of higher dose mafosfamide. MRI imaging at week 10 of study revealed disease recurrence with a 3 cm · 3 cm · 3 cm area of high signal within the resection cavity. The patient was taken back to the operating room for a gross total
surgical resection and the pathology again demonstrated CNS AT/RT. Tumor extending into the left internal capsule and thalamus was resected, resulting in a right hemiparesis. The patient then received modified DFCI/IRS III treatment identical to patient # 2. Therapy was well tolerated with the exception of Grade IV myelosuppression and repeat bacteremic episodes, which necessitated central line removal/replacement. Patient 3 continues to be clinically well with a right hemiparesis. Serial MRI imaging has been negative for residual or recurrent tumor, 2 years 9 months from the time of recurrence. Patient 4 This previously healthy 11 year old male presented after a brief history of progressive headache and visual changes. MRI of the brain revealed a large heterogeneous mass located in the right parietal lobe. He underwent two operations resulting in a gross total surgical resection. Pathology as reviewed at Children’s Hospital Boston and confirmed elsewhere demonstrated a CNS AT/RT and revealed an abnormal karyotype. This included a derivative chromosome 22 which appeared to have resulted in a deletion of 22q11.2 to 22qter, an area which has been implicated in the pathogenesis of AT/RT. Metastatic workup including an MRI of the spine, CSF cytology, abdominal CT and a bone marrow aspirate and biopsy was negative. A repeat brain MRI obtained immediately prior to initiating therapy revealed an increase in peripheral enhancement within the resection cavity. Therapy was initiated based upon DFCI/IRS III. Cycles of chemotherapy were administered as presented in Case 1. MRI imaging obtained after two cycles of chemotherapy revealed decreased enhancement. Craniospinal irradiation to a dose of 3600 cGy with a boost to the tumor bed to a total dose of 5400 cGy was administered concurrently with continuation of DFCI/IRS III based chemotherapy. Serial MRI imaging has been negative for residual/recurrent tumor 20 months from diagnosis. Patient 4 experienced grade IV myelosuppression, vincristine induced peripheral neuropathy, Fanconi’s Syndrome and significant weight loss/anorexia requiring placement of a gastrostomy tube. He developed progressive deterioration in visual acuity a few months into therapy, thought to be optic nerve injury related to significant hydrocephalus at the time of presentation, which has been previously reported [13–15] although vincristine toxicity could not be excluded [16,17]. A decision was made to omit vincristine from his subsequent treatment and his visual acuity stabilized.
Discussion AT/RT of the CNS have an exceedingly poor prognosis, with only seven long-term survivors reported in the literature (Table 4). Information presented at the NCI Workshop [1] incorporating data from the rhabdoid
81 Table 4. Published literature of CNS AT/RT Reference
Age at diagnosis
Sex
Tumor location
Treatment
Outcome
Agranovitch et al. [22] Arrazola et al. [23] Behring et al. [24]
33 months 20 years 8 months 22 months 4 months 6 months 12 months 3 months 3 months 24 months Newborn 4 years 18 months
m m m m f m f m m m m m f
L frontoparietal L frontoparietal L temporoparietal Intraspinal L hemisphere Fourth vent, kidney Post fossa, spinal Infratentorial Parietal Vermis L hemisphere Vermis Vermis
DOD 8 months NED 24 months DOD 10 months DOD 18 months DOD 9 months DOD 2 months DOD 5 months DOD 2 weeks DOD 2.5 months DOD 7.5 months DOD 2 weeks DOD 2.5 months DOD 8 months
5 years 8 months 18 years 14 years 7 years 16 months 25 months
m m m f m m m
5 months
f
Cerebellum Post fossa, kidney L frontal R temporoccipital L parietal Posterior fossa Frontal lobes bilateral + mets Left cerebellar
De Mot et al. [35]
4 weeks 1 years
m m
Guler et al. [36] Hanna et al. [37]
6 years 8 months
m m
Cerebellar Posterior fossa + mets L parietal Frontal horn
STR, 55 Gy, Cis, Adria GTR, CSI GTR, 35 Gy/20 Gy b, chemo STR, 30 Gy/20 Gy b, chemo STR GTR, Cy,VP, Cis,V SRT, chemo Biopsy Biopsy STR, chemo R STR, 36 Gy br/25 Gy sp STR, 36 Gy br/26 Gy sp, IT M Biopsy, 14 Gy R, chemo GTR, ?XRT, chemo STR, 60 Gy relapse STR, XRT, chemo Sx, XRT, chemo R, 27 Gy CSI, 40 Gy B, V, cyclo, Act-D, dox STR, Eto, cis, V, dox, ifos, cyclo, IT thio Eto, cis Biopsy, chemo
DOD 13months DOD 15 months
24 months
f
Parietal
6 years 10 weeks 39 months 18 months 4 years 3 years 4 years 21 years 3 years 5 months 6 years 5 months
f f m m m f m m m m m f
Lateral vent Post fossa Cerebellar Pineal Midline Frontal Post fossa+ L temporal L frontoparietal Post fossa Frontoparietal Right cerebral
GTR, CSI, chemo GTR, 50 Gy, Cyclo, Eto, Cis, V STR, 49.5 Gy, V, IT M, must GTR, 62.5 Gy, IF, Eto, Car STR, chemo STR, XRT, chemo, ASCR STR, XRT, chemo, ASCR STR, XRT, chemo Biopsy R, 13.4 Gy STR, 60 Gy STR, XRT STR, steroids STR, XRT STR, 8-in-1
3 years 4 years
