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High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Children and Adults With Newly Diagnosed Pineoblastomas

Sridharan Gururangan, Colleen McLaughlin, Jennifer Quinn, Jeremy Rich, David Reardon, Edward C. Halperin, James Herndon, II, Herbert Fuchs, Timothy George, James Provenzale, Melody Watral, Roger E. McLendon, Allan Friedman, Henry S. Friedman, Joanne Kurtzberg, James Vredenbergh, Paul L. Martin

From the Brain Tumor Center at Duke and the Departments of Pediatrics, Radiation Oncology, Neurology, Neurosurgery, Pathology, Neuro-radiology, Family and Community Medicine, and Bone Marrow Transplantation, Duke University Medical Center, Durham, NC.

Address reprint requests to Sridharan Gururangan, MRCP (UK), The Brain Tumor Center at Duke University Medical Center, Box 3624, DUMC, Durham, NC 27710; email: gurur002{at}mc.duke.edu.

	ABSTRACT

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Purpose: We evaluated the usefulness of a treatment regimen that included high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) in patients with newly diagnosed pineoblastoma (PBL).

Patients and Methods: Twelve patients with PBL were initially treated with surgery and induction chemotherapy. All but two patients underwent radiotherapy. Subsequently, all patients received HDC using cyclophosphamide (CTX) + melphalan (MEL) or busulfan (Bu) + MEL regimens and ASCR.

Results: A total of six children and six adults with median ages of 4.2 (range, 0.3 to 19.8 years) and 23 years (range, 23 to 43.7 years), respectively, were treated according to this strategy. Four patients had metastatic disease confined to the neuraxis. Five of 12 patients (42%) had a complete tumor resection at diagnosis. Ten patients received radiotherapy at median doses of 36.0 and 59.4 Gy to the neuraxis and pineal region, respectively. Eleven patients received HDC with CTX + MEL, and one patient received BU + MEL followed by ASCR. Nine patients are alive with no evidence of disease recurrence at a median of 62 months from diagnosis (range, 28 to 125 months), including three patients with metastatic disease and two infants who did not receive any radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months from diagnosis, respectively. The actuarial 4-year progression-free and overall survivals are 69% (95% confidence interval [CI], 39% to 99%) and 71% (95% CI, 43% to 99%), respectively.

Conclusion: The use of HDC in addition to radiotherapy seems to be an effective treatment for patients with newly diagnosed pineoblastoma.

	INTRODUCTION

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PINEOBLASTOMAS ARE malignant embryonal tumors that arise from the pineal parenchyma and are classified under the group of supratentorial primitive neuroectodermal tumors (PNETs).^1–3 The incidence of pineoblastomas is approximately 3% to 10% of all primary malignant brain tumors in all age groups. The use of conventional chemotherapy and irradiation in children and adults with newly diagnosed pineoblastoma has been extensively reported in the literature.^3–11 Pineoblastomas are high-risk brain tumors with a propensity for frequent relapse. Although one landmark cooperative group study demonstrated survival in excess of 60% with conventional chemotherapy and radiotherapy,⁴ the progression-free survival (PFS) for these patients in most studies has been less than 50% using these modalities.^5,6,8,9 In addition, infants with pineoblastoma and those with metastatic disease have been noted to have a dismal prognosis.^{3–6,10–12}

In recent years, high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) has been used successfully in a selected group of patients with newly diagnosed and recurrent malignant brain tumors.^13–15 The rationale for high-dose chemotherapy is based on the premise that there is a steep dose-response curve for certain chemotherapeutic drugs, particularly alkylating agents such as nitrosoureas, cyclophosphamide (CTX), and melphalan (MEL).¹⁶ The effectiveness of this strategy is based on the chemosensitivity of the tumor and the presence of minimal residual disease at the time of HDC. On the basis of our observation of responses to single-agent CTX and MEL in patients with pineoblastoma,^9,17 we have routinely treated such patients at the time of diagnosis with CTX in addition to radiotherapy followed by HDC using CTX + MEL or busulfan (Bu) + MEL regimens with ASCR. This report summarizes the results of our experience with this strategy and demonstrates its usefulness, particularly in young children who had been able to avoid radiotherapy and those with metastatic disease.

	PATIENTS AND METHODS

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Between 1991 and 2000, a total of 13 patients (seven children and six adults) were diagnosed with pineoblastoma at Duke University Medical Center (Durham, NC). Twelve patients underwent HDC with ASCR after induction chemotherapy and radiotherapy and form the basis of this report, which reflects their status as of August 2002. One patient aged 8 years at diagnosis with metastatic pineoblastoma underwent standard induction chemotherapy and radiotherapy but did not receive HDC with ASCR because of physician choice. This patient has subsequently died 3 years after completion of therapy and is not included in the outcome analysis. Four of 12 patients (patients 7 to 10, Table 1) in this study have appeared in two reports from our institution.^9,15 Informed consent as approved by the local institutional review board was obtained from all patients before commencement of treatment.

Induction Chemotherapy, Radiotherapy, and HDC With ASCR
Details of type and dosage schedules of induction chemotherapy, radiotherapy, bone marrow collection procedures, and HDC used in these patients are summarized in Table 2. Response assessment was made by assessing tumor size (derived from the product of the maximal tumor diameters) on a gadolinium-enhanced MRI of brain or spine obtained regularly during treatment. Response criteria were as follows: complete response (CR) was disappearance of all tumor and no new lesions, partial response (PR) was 50% reduction in tumor size, minimal response (MR) was 25% to 50% reduction in tumor size, stable disease (SD) was less than 25% increase or decrease in tumor size, and progressive disease (PD) was 25% increase in tumor size or appearance of new lesions.

Statistical Analysis
Overall survival (OS) and PFS and were determined using the Kaplan-Meier product limit method.¹⁹ OS was calculated from the date of diagnosis until death from any cause or last follow-up. PFS was calculated from the date of diagnosis until death caused by disease progression, death from any cause, or last follow-up. Differences in survival between groups were determined using the log-rank test.

	RESULTS

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Patient Characteristics and Treatment
Patient characteristics are listed in Table 1. There were six children and six adults enrolled onto this study. The median age at diagnosis was 4.2 years for the children (range, 0.3 to 19.8 years) and 23 years for the adults (range, 23 to 43.7 years). Four young children (patients 1 to 4; Table 1) with bilateral retinoblastoma developed a second primary tumor in the pineal region that was found to be pineoblastoma on histology. Four patients (patients 4, 5, 9, and 11; Table 1) had metastatic disease at diagnosis confined to the neuraxis. Two patients (patients 9 and 11; Table 1) had nodular metastatic disease confined to the brain (M-2 disease). In one of these patients (patient 11), the neurosurgeon observed nodular disease along the infundibulum and wall of ventricle III during initial ventriculoscopic biopsy of the pineal tumor. The CSF in this patient was also positive for malignant cells; however, MRI brain and spine were negative for metastatic disease. Two other patients (patients 4 and 5; Table 1) had positive CSF only (M-1 disease) and extensive nodular disease involving brain and spine (M-3 disease), respectively. Five of 12 patients (42%; patients 1, 2, 6, 7, and 11; Table 1) underwent complete resection of the primary tumor at diagnosis. Nine patients received induction therapy per regimen A, two patients received regimen B, and one patient received regimen C as indicated in Tables 1 and 2. All patients, except two infants, received standard craniospinal irradiation with a focal boost to the pineal region. Radiotherapy was deliberately withheld in two infants to avoid the deleterious effects of radiation to the growing brain. The median dose of radiotherapy to the neuraxis was 36 Gy (range, 36 to 46.2 Gy) and the pineal region received a median maximum dose of 59.4 Gy (range, 56 to 66 Gy). Eleven patients received HDC with CTX + MEL and one patient received Bu + MEL followed by ASCR (Table 1).

Responses to Induction and HDC
Responses to induction chemotherapy are listed in Table 1. Of seven patients assessable for responses, one patient achieved CR, five patients achieved PR, and one patient achieved SD to this treatment, with an objective response (CR + PR) rate of 86% (95% confidence interval [CI], 60% to 100%).

Of six patients who were subsequently assessable for responses to HDC, two patients achieved CR, one patient achieved PR, and three patients achieved SD to this therapy, with an objective response rate of 50% (95% CI, 10% to 90%).

Treatment-Related Toxicity
Induction chemotherapy and radiotherapy. No unexpected acute toxicities were encountered during induction chemotherapy or radiotherapy in any patient other than pancytopenia requiring G-CSF and blood product support. The toxicity related to high-dose CTX in some of our patients has been reported previously.^9,20

HDC. Nine patients received bone marrow plus PBSC and three patients received PBSC only. The median stem-cell dose infused was 1.2 x 10⁸ cells/kg body weight (range, 0.2 to 14.4). In 11 assessable patients, the median time for recovery of absolute neutrophil count to 500/mm³ and platelet count 50,000/mm³ after HDC was 12 (range, 9 to 16 days) and 24 days (range, 24 to 65 days), respectively.

Other adverse events associated with HDC included grade 2 to 4 mucositis in 11 patients, bacteremia in two patients, gastrointestinal hemorrhage (grade 2) in one patient, subdural hematoma in one patient, and grade 4 veno-occlusive disease in one patient (patient 5; Table 1). The patient with veno-occlusive disease recovered completely after treatment with defibrotide and supportive care. This patient also had a focal seizure and transient monoplegia of the left upper limb almost 18 months after completion of treatment. On MRI and angiographic studies, decrease in flow in a segment of the right middle cerebral artery was noted without any ischemic changes in the cerebral parenchyma. The patient has since remained symptom free while taking daily low-dose aspirin and dipyridamole. There were no treatment-related deaths.

Outcome and Survival
Nine patients are alive and disease-free at a median follow-up of 62 months (range, 28 to 125 months) from diagnosis. This includes three of four patients with metastatic disease at presentation (patients 5, 9, and 11; Table 1) and two infants (patients 1 and 2; Table 1) who did not receive radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months, respectively, after diagnosis. Sites of progression were in the local and metastatic sites in two patients and metastatic site alone in one patient (patients 3, 4, and 8; Table 1). Two of eight patients with localized disease suffered progressive disease compared with one of four patients with metastatic disease.

The actuarial 4-year PFS and OS are 69% (95% CI, 39% to 99%) and 71% (95% CI, 43% to 99%), respectively (Fig 1). The 4-year PFS for patients with localized disease was 75% (95% CI, 75% to 100%) compared with 75% (95% CI, 75% to 100%) in patients with metastatic disease (Fig 2).

View larger version (14K): [in this window] [in a new window]   Fig 1. Overall survival (OS) and progression-free survival (PFS) in 12 children with newly diagnosed pineoblastomas.

View larger version (12K): [in this window] [in a new window]   Fig 2. Progression-free survival (PFS) in patients with newly diagnosed pineoblastoma by extent of disease (local v metastatic).

	DISCUSSION

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Six of seven patients (86%) assessable for response to induction therapy had an objective response to this treatment. Our rationale for using a CTX or a CTX-based regimen was based on the favorable activity of this agent in PNETs and was designed to overcome alkylator resistance in tumors by using high doses of CTX along with G-CSF support.^{9,13,20,27,28} Almost all patients received CTX + MEL as HDC before ASCR and their use was based on preclinical and clinical evidence of favorable activity of bifunctional alkylating agents, including MEL and CTX against PNET, differing nonhematologic toxicities, and potential synergism when combined.^29–31 The efficacy of this HDC regimen is particularly apparent in the 50% response rate after HDC, and the salvage therapy of three patients with metastatic pineoblastoma and two young children with trilateral retinoblastoma who were also able to avoid radiotherapy. These patients have a particularly poor survival with conventional treatment alone.^5,6,8,11,12 Other studies have reported that the use of HDC in patients with pineoblastoma also has prolonged survival, especially in patients with newly diagnosed tumors.^13,15,27 This is in distinct contrast to the lack of efficacy of this strategy in those with recurrent disease.^15,32

Although conventional treatment has been shown to cure some patients with localized pineoblastoma,^4,6,12 it has had limited success in infants and those with metastatic disease.^4–8,11,12 In addition, the use of neuraxis irradiation in some long-term survivors younger than 9 years of age has resulted in significant developmental delays.⁴

Five of 12 patients (42%) in our study had complete resection of tumor. All of these patients are currently alive without evidence of tumor after radiotherapy and HDC. It is possible that the extent of resection could have contributed to the long-term survival of these patients. Conversely, four of seven patients in our study who had only a biopsy or subtotal resection of tumor also have had extended disease-free intervals. The value of the extent of tumor resection in patients with pineoblastoma has not been systematically addressed, as it has been in those with medulloblastoma.³³

All but two patients in our study received standard doses of radiotherapy before HDC. On the basis of previous reports of successful outcomes in patients with localized pineoblastoma with standard chemotherapy and irradiation,^3,4,6,12 it could be argued that some patients with localized disease in our study who received standard radiotherapy could have been cured without the use of HDC. Although the role of HDC in the cure of such patients cannot be completely resolved, it is likely that there is a subgroup of patients with nonmetastatic pineoblastoma, particularly infants, who nevertheless progress during standard treatment and who might benefit from chemotherapy dose-intensification.^13,27 In addition, on the basis of our report, it is possible to envisage future studies aimed at avoiding or reducing the neuraxis dose in these patients in the context of HDC.^13,32 It also should be noted that some patients in our study (including one patient with M-3 disease) received a higher dose of radiotherapy (focal 60 to 66 Gy, craniospinal irradiation [CSI], up to 45 Gy) that could have contributed to a favorable outcome in these patients. However, the use of similar doses of radiotherapy in other reported series failed to improve survival, particularly in patients with neuraxis dissemination.^5,12

Toxicities in this study were fairly predictable and successfully managed with supportive care in the majority of patients. As expected, the predominant toxicity was myelosuppression, which in turn led to mucositis, infections, and bleeding tendencies. It is noteworthy that there were no toxic deaths in our study, even though toxic mortality rates of 6% to 15% have been reported in other HDC studies.^14,32,34

Pineoblastoma is an aggressive embryonal tumor and is characterized as a high-risk PNET. Although some studies have demonstrated durable disease remission in patients with localized disease with standard treatment, there seems to be a subset of patients with localized disease who suffer progressive disease during therapy probably because of innate resistance to chemotherapy or irradiation. Our study demonstrates that such patients might benefit from up-front dose-intensification with HDC. In addition, based on our experience, this strategy should be considered in the initial treatment of infants and those with metastatic disease at diagnosis or trilateral retinoblastoma.

	NOTES

 
Presented in part at the Society of Neuro-Oncology Meeting, Washington, DC, November 15–18, 2001.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Duffner PK, Cohen ME, Myers MH, et al: Survival of children with brain tumors: SEER Program, 1973–1980. Neurology 36:597–601, 1986[Abstract/Free Full Text]

2. Rickert CH: Epidemiological features of brain tumors in the first 3 years of life. Childs Nerv Syst 14:547–550, 1998[CrossRef][Medline]

3. Jakacki RI: Pineal and nonpineal supratentorial primitive neuroectodermal tumors. Childs Nerv Syst 15:586–591, 1999[CrossRef][Medline]

4. Jakacki RI, Zeltzer PM, Boyett JM, et al: Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: A report of the Childrens Cancer Group. J Clin Oncol 13:1377–1383, 1995[Abstract]

5. Reddy AT, Janss AJ, Phillips PC, et al: Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 88:2189–2193, 2000[CrossRef][Medline]

6. Timmermann B, Kortmann RD, Kuhl J, et al: Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: Results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20:842–849, 2002[Abstract/Free Full Text]

7. Prados MD, Wara W, Edwards MS, et al: Treatment of high-risk medulloblastoma and other primitive neuroectodermal tumors with reduced dose craniospinal radiation therapy and multi-agent nitrosourea-based chemotherapy. Pediatr Neurosurg 25:174–181, 1996[Medline]

8. Mikaeloff Y, Raquin MA, Lellouch-Tubiana A, et al: Primitive cerebral neuroectodermal tumors excluding medulloblastomas: A retrospective study of 30 cases. Pediatr Neurosurg 29:170–177, 1998[CrossRef][Medline]

9. Ashley DM, Longee D, Tien R, et al: Treatment of patients with pineoblastoma with high dose cyclophosphamide. Med Pediatr Oncol 26:387–392, 1996[CrossRef][Medline]

10. Cohen BH, Zeltzer PM, Boyett JM, et al: Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: A Children’s Cancer Group randomized trial. J Clin Oncol 13:1687–1696, 1995[Abstract/Free Full Text]

11. Duffner PK, Cohen ME, Sanford RA, et al: Lack of efficacy of postoperative chemotherapy and delayed radiation in very young children with pineoblastoma: Pediatric Oncology Group. Med Pediatr Oncol 25:38–44, 1995[Medline]

12. Chang SM, Lillis-Hearne PK, Larson DA, et al: Pineoblastoma in adults. Neurosurgery 37:383–390, 1995[Medline]

13. Mason WP, Goldman S, Yates AJ, et al: Survival following intensive chemotherapy with bone marrow reconstitution for children with recurrent intracranial ependymoma: A report of the Children’s Cancer Group. J Neurooncol 37:135–143, 1998[CrossRef][Medline]

14. Finlay JL: The role of high-dose chemotherapy and stem cell rescue in the treatment of malignant brain tumors: A reappraisal. Pediatr Transplant 3:87–95, 1999

15. Graham ML, Herndon JE II, Casey JR, et al: High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors. J Clin Oncol 15:1814–1823, 1997[Abstract/Free Full Text]

16. Frei E III, Teicher BA, Holden SA, et al: Preclinical studies and clinical correlation of the effect of alkylating dose. Cancer Res 48:6417–6423, 1988[Abstract/Free Full Text]

17. Friedman HS, Schold SC Jr, Mahaley MS Jr. et al: Phase II treatment of medulloblastoma and pineoblastoma with melphalan: Clinical therapy based on experimental models of human medulloblastoma. J Clin Oncol 7:904–911, 1989[Abstract]

18. Mclendon RE, Enterline DS: Tumors of specialized tissues of central neuroepithelial origin, in Bigner DD, McLendon RE, Bruner JM (eds): Russell and Rubinstein’s Pathology of Tumors of the Nervous System. New York, NY, Oxford University Press, 1998, pp 25–30

19. Kaplan EL, Meier, P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–480, 1958[CrossRef]

20. Moghrabi A, Fuchs H, Brown M, et al: Cyclophosphamide in combination with sargramostim for treatment of recurrent medulloblastoma. Med Pediatr Oncol 25:190–196, 1995[Medline]

21. Mena H, Nakazato Y, Jouvet A, et al: Pineoblastoma, in Kleihues P, Cavenee WK (eds): Pathology and Genetics of Tumors of the Nervous System. Lyon, France, IARC Press, 2000, pp 116–120

22. Russo C, Pellarin M, Tingby O, et al: Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 86:331–339, 1999[CrossRef][Medline]

23. Packer RJ, Cogen P, Vezina G, et al: Medulloblastoma: Clinical and biologic aspects. Neuro-oncol 1:232–250, 1999[Abstract]

24. Schild SE, Scheithauer BW, Schomberg PJ, et al: Pineal parenchymal tumors: Clinical, pathologic, and therapeutic aspects. Cancer 72:870–880, 1993[CrossRef][Medline]

25. Lutterbach J, Fauchon F, Schild SE, et al: Malignant pineal parenchymal tumors in adult patients: Patterns of care and prognostic factors. Neurosurgery 51:44–56, 2002[CrossRef][Medline]

26. Kivela T: Trilateral retinoblastoma: A meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17:1829–1837, 1999[Abstract/Free Full Text]

27. Strother D, Ashley D, Kellie SJ, et al: Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: Results of a collaborative study. J Clin Oncol 19:2696–2704, 2001[Abstract/Free Full Text]

28. Allen JC, Helson L: High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55:749–756, 1981[Medline]

29. Friedman HS, Colvin OM, Skapek SX, et al: Experimental chemotherapy of human medulloblastoma cell lines and transplantable xenografts with bifunctional alkylating agents. Cancer Res 48:4189–4195, 1988[Abstract/Free Full Text]

30. Schabel FM Jr, Trader MW, Laster WR Jr, et al: Patterns of resistance and therapeutic synergism among alkylating agents. Antibiot Chemother 23:200–215, 1978[Medline]

31. Mahoney DH Jr, Strother D, Camitta B, et al: High-dose melphalan and cyclophosphamide with autologous bone marrow rescue for recurrent/progressive malignant brain tumors in children: A pilot pediatric oncology group study. J Clin Oncol 14:382–388, 1996[Abstract/Free Full Text]

32. Guruangan S, Dunkel IJ, Goldman S, et al: Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors. J Clin Oncol 16:2486–2493, 1998[Abstract]

33. Albright AL, Wisoff JH, Zeltzer PM, et al: Effects of medulloblastoma resections on outcome in children: A report from the Children’s Cancer Group. Neurosurgery 38:265–271, 1996[CrossRef][Medline]

34. Dunkel IJ, Boyett JM, Yates A, et al: High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma: Children’s Cancer Group. J Clin Oncol 16:222–228, 1998[Abstract/Free Full Text]

Submitted October 18, 2002; accepted March 13, 2003.

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