0360.3016/90 $3.00 + .I0 Copyright (c I990 Pergamon Press plc
l Original Contribution
PINEAL
DEREK MARK ROBIN
JENKIN,
M.B.,‘T~
GREENBERG, HUMPHREYS,
REGION GERMINOMAS IN CHILDHOOD TREATMENT CONSIDERATIONS
M.D.,’ M.D.,2
MARTIN
BRUCE MARILYN
BERRY,
HENDRICK, SONLEY,
M.B., M.D.,* M.D.’
1.3 HELEN
CHAN,
HAROLD AND SHEILA
M.D.,’
HOFFMAN, WEITZMAN,
M.D.,* M.D.’
‘Department of Paediatrics, Division of Haematology/Oncology, ‘Department of Surgery, Division of Neurosurgery, The Hospital For Sick Children, Toronto; and 3Toronto-Bayview Regional Cancer Centre/Sunnybrook Medical Centre, University of Toronto From 1967-1986,21 children were treated for pineal germinoma, including 16 biopsy-proven, 2 biopsy non-diagnostic, unbiopsied (marker negative) patients. Ten of 18 (56%) biopsied patients underwent partial or sub-total tumor resection. Twenty patients were irradiated, 19 of whom are alive. No irradiated patient died of progressive germinoma, but two patients relapsed in the spinal cord and required treatment intensification for salvage. Long-term survivors have significant morbidity. Determination of the minimum effective treatment remains the chief therapeutic challenge.
and 3 metastatic
Pineal germinoma, radiation treatment. INTRODUCTION
comprehensive for our geographic region which has a population of approximately 3.0 million. For a patient to be included in this series it was necessary that a germinoma was identified in the pineal region. Patients with, in addition, germinoma in the suprasellar region or at any other site were included, but patients with germinoma in the suprasellar region alone were excluded, due to their rather different natural history. Fifty consecutive previously untreated children were identified with a pineal region mass lesion which was assumed to be a tumor. A tissue diagnosis was available in 35/50 (70%). Prior to 1967 the diagnosis of pineal region tumor was made on the basis of the clinical findings and an air study. Biopsy was not undertaken (10 patients). Since 1967 biopsy has been undertaken routinely, 37140 (92%) patients. The distribution of patients by histological diagnosis is given in Table 1. Sixteen of 37 (43%) patients were confirmed as germinomas, 8137 (22%) had nongerminomatous germ cell tumors, and 1 l/37 (30%) had other tumors. In 2137 (5%) the biopsy was non-diagnostic. Since these two patients had normal levels of alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) they were treated as germinomas. The three patients not biopsied since 1967 had brain metastases at diagnosis and biopsy was not considered to be justified. Since they also were marker negative they were treated as germinomas. Overall since 1967, 40 children were seen with pineal re-
Treatment results in patients with pineal region tumors have been reported previously from the Toronto Region (7, 8, 10). The stimulus for this review of germinomas of the pineal region in childhood resulted from the need to critically re-examine treatment methods in the light of additional experience with initial resection and post-operative craniospinal irradiation and, when necessary, chemotherapy and re-irradiation for salvage from relapse. While such treatment is successful in eradicating germinoma, there is concern that it might be unnecessarily intensive. Nearly all children with this malignancy survive. Might it be possible to improve subsequent quality of life by modifying the initial treatment strategy?
METHODS
AND
MATERIALS
Children less than 17-years old with a pineal region tumor diagnosed during the years 1959-86 inclusive, were identified by review of the records of The Hospital For Sick Children, The Princess Margaret Hospital and the Toronto-Bayview Regional Cancer Centre. In the Metropolitan Toronto Region nearly all pediatric neurosurgery is undertaken at The Hospital For Sick Children and all radiation treatment is carried out at one of the other two centers. Therefore, we believe that this data base is
Accepted for publication
Reprint requests to: R. D. T. Jenkin, M.B., Toronto-Bayview Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada. 541
12 September
1989.
542
I. J. Radiation Oncology 0 Biology 0 Physics Table I. Pineal region tumors:
histological
Germinoma Proven Biopsy non-diagnostic Endodermal sinus tumor Choriocarcinoma Other histologies PNET Astrocytoma Teratoma (MAL 3, BEN 1)
diagnosis
18 16 2 2 2 15 I 4 4 31
tumors, 16 (43%) were proven to be germinomas and 2 I (52%) were treated as germinomas. In this review the 2 1 patients seen since 1967 with a proven or clinical diagnosis of germinoma are analyzed. CT became available to us in 1974 and was used routinely thereafter in patients with pineal region tumors. The age range was 3-16 years (mean 11. median 12 years). Only one child was less than 7 years old. Eighteen of 2 I (86%) were 9-14 years old. Nineteen of 2 1 (90%) were boys. Four of 2 1 (19%) patients were demonstrated by CT scan at diagnosis to have other local tumor sites (suprasellar region 2 patients: thalamic/hypothalamic region 2 patients). An additional patient had diffuse tumor frosting of the lateral and third ventricles at diagnosis. Six of 2 1 (29%) patients had diabetes insipidus at diagnosis. Four of these patients had demonstrable tumor in the suprasellar or thalamic regions. However, symptomatic overt metastatic disease was not encountered at diagnosis. Elective myelography was only recently introduced in Toronto, and two such examinations were negative. The cerebrospinal fluid (CSF) of two recent patients was positive for malignant cells, but the denominator for this observation was uncertain. CSF and/or serum HCG and AFP levels were available in six patients (5 unverified) with germinoma and all were normal.
gion
Surgical treatment All patients presented with increased intracranial pressure. In 1S/2 1 (86%) patients, a shunt was required as the first treatment. In 10/l 8 (56%) biopsied patients, a partial or subtotal tumor resection was undertaken. There were no operative deaths. One verified patient who was deeply comatose postoperatively was not irradiated. He died of progressive disease 11 months after resection, without recovering consciousness. The surgical procedures have been described previously (7, 8). Radiation treatment Twenty of 2 1 (95%) patients were irradiated. Radiation data were unavailable in one irradiated patient. The volume irradiated was a generous local region in 5 patients
March
1990. Volume
18,Number 3
(25%). the local region and the whole brain in 4 patients (20%), and the local region and the craniospinal axis in IO patients (50%). The choice of the volume to be irradiated was dependent on the year of diagnosis. From 1967-76 the volume was local in 2/9 (22%), local and whole brain in 4/9 (44%), and local and craniospinal axis in 3/9 (33%). From 197786 the volume irradiated was local in 3/ 10 (30%), local and whole brain in none, and local and craniospinal axis in 7/10 (70%). The radiation dose to the primary tumor was 4-4500 cGy in 4/19 (22%), 5000 cGy in IO/l9 (55%), 5080-5250 cGy in 4/ 19 (220/o), and 5500 cGy in 1 patient. Radiation was given in daily fractions of approximately 200 cGy 5 days per week. The dose to the whole brain was 0 in 5/19 (26%), 22500 cGy in 4/19 (22%), 3-3500 cGy in 7/19 (37%), and 36-4000 cGy in 3/ 19 ( 16%) patients. The dose to the spine was 0 in 9/19 (48%), 2-2500 cGy in 3/ 19 ( 16%), 3-3500 cGy in 5/ 19 (26%), and 36-4000 cGy in 2/29 ( 1 1%) patients. The elective spine and whole brain doses were the same. The daily fraction size was 180-200 cGy. Chemotherapy Only l/2 1 patients received elective chemotherapy. This was a recent patient with diffuse tumor frosting of the ventricles at diagnosis who was electively treated with combination chemotherapy (Cis-Platinum, Etoposide and Bleomycin) before and after craniospinal irradiation. He remains in first complete remission 36+ months from diagnosis. An additional patient received vincristine and CCNU during local irradiation because he developed root pain without evidence of spinal seeding (9). Gross relapse was detected in the spine after one cycle of chemotherapy, before the planned spinal radiation treatment was commenced. He was salvaged by craniospinal radiation and continued the same chemotherapy. He is alive in continuous complete remission 109+ months from relapse. RESULTS Survival The
5-year
survival
and
relapse-free
survival
rates
for
the 2 1 patients with pineal germinoma were 90% and 85%, respectively (Fig. 1). No subsequent adverse events occurred between 5 and 15 years from diagnosis. There were two deaths. One occurred in the unirradiated patient at 1 1 months. The second was in a patient with diabetes insipidus who had both pineal region and thalamic tumor and was treated with craniospinal irradiation. Sudden death occurred at home 2 months after diagnosis. Autopsy showed no residual tumor, and the cause of death was unclear. Acute hypematremia was suspected. Two patients in addition to the unirradiated one demonstrated progressive disease. They relapsed in the spine and spine plus cerebral meninges, respectively. Both these patients have been salvaged as reported previously (9). At last follow-
543
Pineal region germinomas 0 D. JENKINet al.
Fig. 1. Pineal germinomas (N = 2 1). Overall survival (OS) and relapse-free survival (RFS).
up, they were disease-free 97+ and 109+ months from relapse. Thus, none of 20 irradiated patients have died of progressive germinoma. In contrast to this recent experience the survival and relapse-free survival rates for the 10 children clinically diagnosed from 1958- 1975 as having a “pinealoma” were 100% and 78% at 5 years, 89% and 78% at 10 years, and 74% and 78% at 15 years (Fig. 2). Two of 10 patients relapsed and subsequently died. Both patients suffered late local relapse at 54 and 60 months, respectively, and died as a consequence of slowly progressive local disease alone at 101 and 128 months.
ically or histologically diagnosed pineal region germinoma. The range of duration of follow-up was l-25 years (median 7.9 years). Endocrine defects were apparent. Seven of 27 (26%) patients developed diabetes insipidus prior to tumor diagnosis. This defect was not improved by effective tumor treatment. Hypopituitarism developed in 6127 (22%) patients who required varying degrees of hormonal replacement therapy. Three of these patients also had diabetes insipidus. Four patients received growth hormone therapy. Growth defects, of moderate degree, could be documented in all patients, but caused no obvious functional impairments and thus were not usually a concern of the patients. Brain damage as a consequence of the tumor and/or its treatment occurred to some extent in all patients. None of our patients attended university. Most are employed in unskilled trades. Difficulty with schooling, lost grades, and the need for special education services were commonplace. One patient was institutionalized with a personality disorder and stable hemiparesis. Two patients were unemployed and lived with their parents. One of these patients was retarded and had seizures which were difficult to control. The other had ataxia and an IQ of 70. Two patients had mild to moderate hearing impairment and one had poor vision. Only 9/27 (33%) of the patients had no gross late effects, other than poorer performance compared with their siblings.
Relupse pattern Two of 19 ( 1 1%) patients relapsed in the spinal meninges. one of whom had simultaneous “local” recurrence as evidenced by a seventh nerve palsy. Both patients had received whole brain and local irradiation only initially. Neither patients had elective myelography. These were early relapses at 2 and 7 months, respectively.
Lute eflkt.7 The morbidity associated with a pineal germinoma and its surgical and radiation treatment is underestimated by retrospective chart review, but by this methodology significant morbidity was noted. Overall follow-up data were available on 27 patients (1959-66, 8 patients; 1967-86, 19 patients) who survived after treatment of either a clin-
Fig. 2. Clinical “pinealomas” (N = 10). Overall survival and relapse-free survival (RFS).
(OS)
DISCUSSION The age distribution of patients in this series is consistent with the literature which reports a peak age incidence of 10 to 12 years for 253 patients with intracranial germinoma at any site (1 1). The male preponderance of 191 2 1 (90%) is high compared to 73% in the literature (11). Of our verified pineal region tumors, germinomas represented 16/24 (67%) of all pineal germ cell tumors and 16/37 (43%) of all pineal tumors. In the literature, germinomas represent 253/389 (65%) of all intracranial germ cell tumors in all ages (11). Conversely, Packer et al. reported that in children pineal region germ cell tumors represent only 32% of all tumors and found only 1 germinoma among 25 consecutive children with pineal tumors (13). The favorable outcome reported when unbiopsied pineal tumors were treated by shunting and local irradiation alone, with 5-year relapse free-survival rates in the range of 50%-88% (1, 3, 4, 6, 9, 13, 14, 15, 16, 17, 19), and our 5-year relapse-free survival rate of 78% for 10 children with unbiopsied tumors, is strong circumstantial evidence that the majority of childhood pineal region tumors are germinomas. If, for example, 50% of pineal region tumors are germinomas and 50% are other tumors with radiocurability rates of 100% and 20%, respectively, then local irradiation of all unverified pineal tumors should be associated with an overall cure rate of 60%. Since the natural histories and treatment response of
544
I. J. Radiation
Oncology
0 Biology 0 Physics
the different histological types of pineal region tumors are diverse, information derived from reports of patients with unbiopsied tumors is of limited value. Pineal region germinoma is a distinct clinical entity. If it is to be treated rationally, an initial histological diagnosis is mandatory. We continue to believe that all pineal region tumors should be biopsied (7, 8). The literature on verified childhood pineal region germinomas, intracranial germ cell tumors, and unverified “pinealomas” was reviewed ( 1, 3,4. 6, 11, 12, 14, 15, 16, 17, 19). Data on 118 verified germinomas were extracted from a total of 381 case reports. Patients were included in this analysis even when their ages and the intracranial sites of the germinoma were not specified. Ninety of 118 (76%) of these patients were alive at the time of reporting. Radiation data were available for 81 patients. Twentyfour (30%) received craniospinal irradiation and 57 (70%) some form of local irradiation without spinal cord irradiation. Relapse patterns were only occasionally reported. Spinal seeding was reported in 7/39 (I 8%) patients. The radiation dose given for primary pineal region tumors of all types was usually in the range of 4500-5500 cGy ( 180200 cGy daily). No author reported routine use of lower radiation doses in verified germinomas. In this series, none of the 10 children treated with craniospinal irradiation relapsed, whereas two spinal relapses occurred among the remaining nine patients in whom the spine was not irradiated. The patients who received craniospinal irradiation were selected, in part, by an assumed increased risk of seeding. Eight of 19 (42%) patients were so categorized, using as adverse factors multiple intracranial tumor sites at diagnosis (4 patients), malignant cells in the CSF (2 patients), and diabetes insipidus (6 patients). Six (75%) of these patients received craniospinal irradiation. Two patients with diabetes insipidus alone were irradiated locally without subsequent relapse. In comparison 4/l 1 (36%) patients without any of these adverse factors underwent elective craniospinal irradiation and of the seven patients treated locally two relapsed in the spine. Additional variation in the use of elective craniospinal irradiation occurred due to uncertainty concerning the occult spinal seeding rate to be anticipated in patients undergoing biopsy with or without resection. Rates as high as 40% have been reported ( 17). Five patients were demonstrated to have multiple tumor sites or dissemination at diagnosis. None have relapsed. All but one (with thalamic involvement) received craniospinal irradiation. The involved regions received 5-5250 cGy and the electively irradiated component of the central nervous system received 2500, 3075, 3500, 4000 cGy, respectively. Two recent large series have provided strong evidence that craniospinal irradiation may not be necessary for most patients with verified pineal germinomas (12, 16). Lindstadt et al. reported on 13 patients with biopsy proven intracranial germinomas (all sites and ages). None relapsed
March
1990. Volume
18. Number
3
after irradiation and only one received elective craniospinal irradiation. In addition 19 unbiopsied patients were treated without craniospinal irradiation and only one developed spinal metastases (12). Therefore. craniospinal irradiation was not recommended unless metastases were present at diagnosis, CSF cytology was malignant or gross tumor spill had occurred at tumor resection. Only I of 13 verified patients required craniospinal irradiation with these indications. Shibamato et al. reported on 70 patients with intracranial germinoma (all sites and ages). of which 42 were verified (histology 30 patients, cytology 12 patients) ( 16). The 5- and lo-year survival rates for verified cases were 84% and 76%, respectively. There was no significant difference in survival between patients treated with local as opposed to craniospinal irradiation, with 5year survival rates of approximately 77% and 84%, respectively, for verified patients and 9 1% and 87% for unverified cases. Results were not given for the patients who were less than 17-years old with pineal region germinomas, nor for verified and unverified patients by tumor site and irradiated volume. However. none of 12 patients (verified and unverified) with tumors in the pineal or pineal and suprasellar regions who received craniospinal irradiation relapsed, compared with 3/26 (12%) patients in whom the volume irradiated was less than the complete craniospinal axis. These authors favored elective craniospinal irradiation when there were multiple sites of tumor at diagnosis or when the CSF cytology was positive, that is. in about 60% of patients due to the very high CSF positivity rates in Japan. If craniospinal irradiation is undertaken selectively for patients with pineal region germinomas, with multiple tumor sites, metastatic seeding, malignant cytology, and diabetes insipidus as the indications, as is our present practice, this series forecasts that 8/ 19 (42%) of patients will be given craniospinal irradiation. In this series no patient with a verified germinoma relapsed in-field after irradiation. Therefore, the dose range of 44.5500 cGy was uniformly successful in tumor control. Included were six patients in whom the radiation dose range was 4-4500 cGy. Clearly. the optimal radiation dose is the lowest effective dose. A parallel might be drawn with germinomas in other locations, such as the testis. Testicular germinomas are successfully treated by irradiation at much lower doses. In the Toronto experience, patients with macroscopic regional spread of testicular germinoma (Stage 2A) treated with large volume irradiation in the dose range of 2-3000 cGy in 20-25 fractions had a 5-year survival rate of 87% ( 18). Low dose radiation was never used to treat unbiopsied pineal tumors, for it was recognized that the tumor mix at this site included some relatively radio-resistant tumors. The local control rate therefore increased with escalation of the radiation dose (17). The optimal radiation dose in verified pineal germinomas remains to be determined and this is an important objective for current pilot studies.
Pineal region germi nomas 0 D. JENKIN et (11.
None of the five unverified “germinomas” among the 2 1 patients reported, including three with dissemination at diagnosis, relapsed; this is excellent confirmation of the correctness of the clinical diagnosis. Significant morbidity occurred in the long-term survivors, mainly in relation to the central nervous system. It is difficult to distinguish damage done by the tumor, both directly and from prolonged raised intracranial pressure, and that due to surgical and radiation treatment. Morbidity due to the tumor can only be decreased by earlier diagnosis but treatment morbidity can be reduced by determining what is the least morbid, yet still effective, treatment and using such treatment. There are good grounds for believing that currently pineal germinomas are being over-treated. In this series it is uncertain whether partial or subtotal tumor resection of a pineal germinoma contributed towards local control, since all our verified patients achieved local control regardless of the extent of the surgical pro-
545
cedure. In uncomplicated patients it may be that small volume low dose local irradiation, in biopsied but not resected pineal germinomas, is just as effective as craniospinal irradiation, with a high dose boost to a large local volume, after tumor resection. This needs to be determined. Should elective chemotherapy be undertaken? We now know that chemotherapy can be curative for testicular germinomas, and that pineal germinomas respond well to similar drug regimens (2, 5). Such regimens are intense and have significant systemic toxicity. Children with pineal germinomas do not need elective combination chemotherapy to increase the cure rate. Pilot studies of combined modality therapy or chemotherapy alone will need to focus on the difficult end point of decreased morbidity, but these too are indicated. In summary, pineal germinomas in children are nearly always cured. It is necessary to determine the method which will achieve this objective with the least morbidity.
REFERENCES E. 0.; Laws, E. R.; Grado, G. L.; Bruckman. J. E.; Forbes, G. S.; Gomez, M. R.: Scott, M. Pineal tumors in
I. Abay,
2.
3.
4. 5. 6.
7.
8.
9.
IO.
children and adolescents. Treatment by CSF shunting and radiotherapy. J. Neurosurg. 55:889-895: 198 I Allen, J. C.: Kim, J. H.; Packer, R. J. Neoadjuvant chemotherapy for newly diagnosed germ cell tumors of the central nervous system. J. Neurosurg. 67:65-70: 1987. Amendola, B. E.; McClatchey, K.; Amendola, M. A. Pineal region tumors: analysis of treatment results. Int. J. Radiat. Oncol. Biol. Phys. 10:991-997; 1984. Bradfield, J. S.; Perez, C. A. Pineal tumors and ectopic pinealomas. Radiology 103:399-406: 1972. De Tribolet, N.; Barrelet, L. Successful chemotherapy of pinealoma. Lancet December 10, 1228-1229; 1977. Griffin, B. R.: Griffin, T. W.; Tong, D. Y. K.; Russel, A. H.; Kurtz, J.: Laramore, G. E.; Groudine, M. Pineal region tumors: results of radiation therapy and indications for elective spinal irradiation. Int. J. Radiat. Oncol. Biol. Phys. 7:605608: 1981. Hoffman, H. J.; Yoshida, M.: Becker, L. E.; Hendrick, E. B.; Humphreys, R. P. Experience with pineal region tumors in childhood. Neurolog. Res. 6:107-l 12; 1984. Hoffman, H. J.; Yoshida, M.: Becker, L. E.; Hendrick, E. B.; Humphreys, R. P. Pineal region tumors in childhood. In: Karger, Base], eds. Concepts pediatric neurosurgery, Vol. 4. Base]: Karger; 1983:360-386. Jenkin, D.; Henkrick, B.; Hoffman, H.; Humphreys, R.; Sonley, M. Pineal and suprasellar germinomas in childhood. In: Severi, L., ed. Tumors of early life in man and animals. Proceedings of the 6th Perugia International Conference on Cancer. Division of Cancer Research. 1977: I- I 1. Jenkin, R. D. T.; Simpson, W. J. K.; Keen, C. W. Pineal and suprasellar germinomas. J. Neurosurg. 48:99-107; 1978.
Il.
12.
13.
14.
15.
16.
17.
18.
19.
Jennings, M. T.; Gelman, R.; and Hochberg, F. Intracranial germ-cell tumors: natural history and pathogenesis. J. Neurosurg. 63:155-167; 1985. Linstadt, D.; Wara, W. M.; Edwards, M. S. B.; Hudgkins, R. J.; and Sheline. G. E. Radiotherapy of primary intracranial germinomas: the case against routine craniospinal irradiation. Int. J. Radiat. Oncol. Biol. Phys. 15:291-297; 1988. Packer, R. J.; Sutton, L. N.; Rosenstock. J. G.; Rorke, L. B.; Bilaniuk, L. T.; Zimmerman. R. A.: Littman, P. A.; Bruce, D. A.; Schut, L. Pineal region tumors of childhood. Paediatrics 74:97-102: 1984. Rao. Y. T. R.; Medini, E.; Haselow, R. E.: Jones, T. K.; and Levitt. S. H. Pineal and ectopic pineal tumors: the role of radiation therapy. Cancer 48:708-7 13; 198 I. Rich, T. A.; Cassady. J. R.; Strand, R. D.; Winston, K. R. Radiation therapy for pineal and suprasellar germ cell tumors. Cancer 55:932-940; 1985. Shibamoto, Y.; Abe, M.; Yamashita, J.; Takahashi, M.: Hiraoka, M.: Ono, K.; Tsutsui, K. Treatment results of intracranial germinoma as a function of the irradiated volume. Int. J. Radiat. Oncol. Biol. Phys. 15:285-290; 1988. Sung, D.; Harisiadis, L.; Chang, C. H. Mid-line pineal tumors and suprasellar germinomas: highly curable by irradiation. Radiology I28:745-75 I : 1978. Thomas, G. M.; Rider, W. D.; Dembo. A. J.; Cummings, B. J.; Gospodarowicz, M.; Hawkins, N. V.: Herman, J. G.; Keen, C. W. Seminoma of the testis: results of treatment and patterns of failure after radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 8: 165-174; 1982. Wara, W. M.; Jenkin. R. D. T.; Evans, A.; Ertel, I.; Hittle, R.; Ortega, J.; Wilson, C. B.; Hammond, D. Tumors of the pineal and suprasellar region: Childrens Cancer Study Group results 1960-75. Cancer 43:698-701; 1979.
l Original Contribution
PINEAL
DEREK MARK ROBIN
JENKIN,
M.B.,‘T~
GREENBERG, HUMPHREYS,
REGION GERMINOMAS IN CHILDHOOD TREATMENT CONSIDERATIONS
M.D.,’ M.D.,2
MARTIN
BRUCE MARILYN
BERRY,
HENDRICK, SONLEY,
M.B., M.D.,* M.D.’
1.3 HELEN
CHAN,
HAROLD AND SHEILA
M.D.,’
HOFFMAN, WEITZMAN,
M.D.,* M.D.’
‘Department of Paediatrics, Division of Haematology/Oncology, ‘Department of Surgery, Division of Neurosurgery, The Hospital For Sick Children, Toronto; and 3Toronto-Bayview Regional Cancer Centre/Sunnybrook Medical Centre, University of Toronto From 1967-1986,21 children were treated for pineal germinoma, including 16 biopsy-proven, 2 biopsy non-diagnostic, unbiopsied (marker negative) patients. Ten of 18 (56%) biopsied patients underwent partial or sub-total tumor resection. Twenty patients were irradiated, 19 of whom are alive. No irradiated patient died of progressive germinoma, but two patients relapsed in the spinal cord and required treatment intensification for salvage. Long-term survivors have significant morbidity. Determination of the minimum effective treatment remains the chief therapeutic challenge.
and 3 metastatic
Pineal germinoma, radiation treatment. INTRODUCTION
comprehensive for our geographic region which has a population of approximately 3.0 million. For a patient to be included in this series it was necessary that a germinoma was identified in the pineal region. Patients with, in addition, germinoma in the suprasellar region or at any other site were included, but patients with germinoma in the suprasellar region alone were excluded, due to their rather different natural history. Fifty consecutive previously untreated children were identified with a pineal region mass lesion which was assumed to be a tumor. A tissue diagnosis was available in 35/50 (70%). Prior to 1967 the diagnosis of pineal region tumor was made on the basis of the clinical findings and an air study. Biopsy was not undertaken (10 patients). Since 1967 biopsy has been undertaken routinely, 37140 (92%) patients. The distribution of patients by histological diagnosis is given in Table 1. Sixteen of 37 (43%) patients were confirmed as germinomas, 8137 (22%) had nongerminomatous germ cell tumors, and 1 l/37 (30%) had other tumors. In 2137 (5%) the biopsy was non-diagnostic. Since these two patients had normal levels of alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) they were treated as germinomas. The three patients not biopsied since 1967 had brain metastases at diagnosis and biopsy was not considered to be justified. Since they also were marker negative they were treated as germinomas. Overall since 1967, 40 children were seen with pineal re-
Treatment results in patients with pineal region tumors have been reported previously from the Toronto Region (7, 8, 10). The stimulus for this review of germinomas of the pineal region in childhood resulted from the need to critically re-examine treatment methods in the light of additional experience with initial resection and post-operative craniospinal irradiation and, when necessary, chemotherapy and re-irradiation for salvage from relapse. While such treatment is successful in eradicating germinoma, there is concern that it might be unnecessarily intensive. Nearly all children with this malignancy survive. Might it be possible to improve subsequent quality of life by modifying the initial treatment strategy?
METHODS
AND
MATERIALS
Children less than 17-years old with a pineal region tumor diagnosed during the years 1959-86 inclusive, were identified by review of the records of The Hospital For Sick Children, The Princess Margaret Hospital and the Toronto-Bayview Regional Cancer Centre. In the Metropolitan Toronto Region nearly all pediatric neurosurgery is undertaken at The Hospital For Sick Children and all radiation treatment is carried out at one of the other two centers. Therefore, we believe that this data base is
Accepted for publication
Reprint requests to: R. D. T. Jenkin, M.B., Toronto-Bayview Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada. 541
12 September
1989.
542
I. J. Radiation Oncology 0 Biology 0 Physics Table I. Pineal region tumors:
histological
Germinoma Proven Biopsy non-diagnostic Endodermal sinus tumor Choriocarcinoma Other histologies PNET Astrocytoma Teratoma (MAL 3, BEN 1)
diagnosis
18 16 2 2 2 15 I 4 4 31
tumors, 16 (43%) were proven to be germinomas and 2 I (52%) were treated as germinomas. In this review the 2 1 patients seen since 1967 with a proven or clinical diagnosis of germinoma are analyzed. CT became available to us in 1974 and was used routinely thereafter in patients with pineal region tumors. The age range was 3-16 years (mean 11. median 12 years). Only one child was less than 7 years old. Eighteen of 2 I (86%) were 9-14 years old. Nineteen of 2 1 (90%) were boys. Four of 2 1 (19%) patients were demonstrated by CT scan at diagnosis to have other local tumor sites (suprasellar region 2 patients: thalamic/hypothalamic region 2 patients). An additional patient had diffuse tumor frosting of the lateral and third ventricles at diagnosis. Six of 2 1 (29%) patients had diabetes insipidus at diagnosis. Four of these patients had demonstrable tumor in the suprasellar or thalamic regions. However, symptomatic overt metastatic disease was not encountered at diagnosis. Elective myelography was only recently introduced in Toronto, and two such examinations were negative. The cerebrospinal fluid (CSF) of two recent patients was positive for malignant cells, but the denominator for this observation was uncertain. CSF and/or serum HCG and AFP levels were available in six patients (5 unverified) with germinoma and all were normal.
gion
Surgical treatment All patients presented with increased intracranial pressure. In 1S/2 1 (86%) patients, a shunt was required as the first treatment. In 10/l 8 (56%) biopsied patients, a partial or subtotal tumor resection was undertaken. There were no operative deaths. One verified patient who was deeply comatose postoperatively was not irradiated. He died of progressive disease 11 months after resection, without recovering consciousness. The surgical procedures have been described previously (7, 8). Radiation treatment Twenty of 2 1 (95%) patients were irradiated. Radiation data were unavailable in one irradiated patient. The volume irradiated was a generous local region in 5 patients
March
1990. Volume
18,Number 3
(25%). the local region and the whole brain in 4 patients (20%), and the local region and the craniospinal axis in IO patients (50%). The choice of the volume to be irradiated was dependent on the year of diagnosis. From 1967-76 the volume was local in 2/9 (22%), local and whole brain in 4/9 (44%), and local and craniospinal axis in 3/9 (33%). From 197786 the volume irradiated was local in 3/ 10 (30%), local and whole brain in none, and local and craniospinal axis in 7/10 (70%). The radiation dose to the primary tumor was 4-4500 cGy in 4/19 (22%), 5000 cGy in IO/l9 (55%), 5080-5250 cGy in 4/ 19 (220/o), and 5500 cGy in 1 patient. Radiation was given in daily fractions of approximately 200 cGy 5 days per week. The dose to the whole brain was 0 in 5/19 (26%), 22500 cGy in 4/19 (22%), 3-3500 cGy in 7/19 (37%), and 36-4000 cGy in 3/ 19 ( 16%) patients. The dose to the spine was 0 in 9/19 (48%), 2-2500 cGy in 3/ 19 ( 16%), 3-3500 cGy in 5/ 19 (26%), and 36-4000 cGy in 2/29 ( 1 1%) patients. The elective spine and whole brain doses were the same. The daily fraction size was 180-200 cGy. Chemotherapy Only l/2 1 patients received elective chemotherapy. This was a recent patient with diffuse tumor frosting of the ventricles at diagnosis who was electively treated with combination chemotherapy (Cis-Platinum, Etoposide and Bleomycin) before and after craniospinal irradiation. He remains in first complete remission 36+ months from diagnosis. An additional patient received vincristine and CCNU during local irradiation because he developed root pain without evidence of spinal seeding (9). Gross relapse was detected in the spine after one cycle of chemotherapy, before the planned spinal radiation treatment was commenced. He was salvaged by craniospinal radiation and continued the same chemotherapy. He is alive in continuous complete remission 109+ months from relapse. RESULTS Survival The
5-year
survival
and
relapse-free
survival
rates
for
the 2 1 patients with pineal germinoma were 90% and 85%, respectively (Fig. 1). No subsequent adverse events occurred between 5 and 15 years from diagnosis. There were two deaths. One occurred in the unirradiated patient at 1 1 months. The second was in a patient with diabetes insipidus who had both pineal region and thalamic tumor and was treated with craniospinal irradiation. Sudden death occurred at home 2 months after diagnosis. Autopsy showed no residual tumor, and the cause of death was unclear. Acute hypematremia was suspected. Two patients in addition to the unirradiated one demonstrated progressive disease. They relapsed in the spine and spine plus cerebral meninges, respectively. Both these patients have been salvaged as reported previously (9). At last follow-
543
Pineal region germinomas 0 D. JENKINet al.
Fig. 1. Pineal germinomas (N = 2 1). Overall survival (OS) and relapse-free survival (RFS).
up, they were disease-free 97+ and 109+ months from relapse. Thus, none of 20 irradiated patients have died of progressive germinoma. In contrast to this recent experience the survival and relapse-free survival rates for the 10 children clinically diagnosed from 1958- 1975 as having a “pinealoma” were 100% and 78% at 5 years, 89% and 78% at 10 years, and 74% and 78% at 15 years (Fig. 2). Two of 10 patients relapsed and subsequently died. Both patients suffered late local relapse at 54 and 60 months, respectively, and died as a consequence of slowly progressive local disease alone at 101 and 128 months.
ically or histologically diagnosed pineal region germinoma. The range of duration of follow-up was l-25 years (median 7.9 years). Endocrine defects were apparent. Seven of 27 (26%) patients developed diabetes insipidus prior to tumor diagnosis. This defect was not improved by effective tumor treatment. Hypopituitarism developed in 6127 (22%) patients who required varying degrees of hormonal replacement therapy. Three of these patients also had diabetes insipidus. Four patients received growth hormone therapy. Growth defects, of moderate degree, could be documented in all patients, but caused no obvious functional impairments and thus were not usually a concern of the patients. Brain damage as a consequence of the tumor and/or its treatment occurred to some extent in all patients. None of our patients attended university. Most are employed in unskilled trades. Difficulty with schooling, lost grades, and the need for special education services were commonplace. One patient was institutionalized with a personality disorder and stable hemiparesis. Two patients were unemployed and lived with their parents. One of these patients was retarded and had seizures which were difficult to control. The other had ataxia and an IQ of 70. Two patients had mild to moderate hearing impairment and one had poor vision. Only 9/27 (33%) of the patients had no gross late effects, other than poorer performance compared with their siblings.
Relupse pattern Two of 19 ( 1 1%) patients relapsed in the spinal meninges. one of whom had simultaneous “local” recurrence as evidenced by a seventh nerve palsy. Both patients had received whole brain and local irradiation only initially. Neither patients had elective myelography. These were early relapses at 2 and 7 months, respectively.
Lute eflkt.7 The morbidity associated with a pineal germinoma and its surgical and radiation treatment is underestimated by retrospective chart review, but by this methodology significant morbidity was noted. Overall follow-up data were available on 27 patients (1959-66, 8 patients; 1967-86, 19 patients) who survived after treatment of either a clin-
Fig. 2. Clinical “pinealomas” (N = 10). Overall survival and relapse-free survival (RFS).
(OS)
DISCUSSION The age distribution of patients in this series is consistent with the literature which reports a peak age incidence of 10 to 12 years for 253 patients with intracranial germinoma at any site (1 1). The male preponderance of 191 2 1 (90%) is high compared to 73% in the literature (11). Of our verified pineal region tumors, germinomas represented 16/24 (67%) of all pineal germ cell tumors and 16/37 (43%) of all pineal tumors. In the literature, germinomas represent 253/389 (65%) of all intracranial germ cell tumors in all ages (11). Conversely, Packer et al. reported that in children pineal region germ cell tumors represent only 32% of all tumors and found only 1 germinoma among 25 consecutive children with pineal tumors (13). The favorable outcome reported when unbiopsied pineal tumors were treated by shunting and local irradiation alone, with 5-year relapse free-survival rates in the range of 50%-88% (1, 3, 4, 6, 9, 13, 14, 15, 16, 17, 19), and our 5-year relapse-free survival rate of 78% for 10 children with unbiopsied tumors, is strong circumstantial evidence that the majority of childhood pineal region tumors are germinomas. If, for example, 50% of pineal region tumors are germinomas and 50% are other tumors with radiocurability rates of 100% and 20%, respectively, then local irradiation of all unverified pineal tumors should be associated with an overall cure rate of 60%. Since the natural histories and treatment response of
544
I. J. Radiation
Oncology
0 Biology 0 Physics
the different histological types of pineal region tumors are diverse, information derived from reports of patients with unbiopsied tumors is of limited value. Pineal region germinoma is a distinct clinical entity. If it is to be treated rationally, an initial histological diagnosis is mandatory. We continue to believe that all pineal region tumors should be biopsied (7, 8). The literature on verified childhood pineal region germinomas, intracranial germ cell tumors, and unverified “pinealomas” was reviewed ( 1, 3,4. 6, 11, 12, 14, 15, 16, 17, 19). Data on 118 verified germinomas were extracted from a total of 381 case reports. Patients were included in this analysis even when their ages and the intracranial sites of the germinoma were not specified. Ninety of 118 (76%) of these patients were alive at the time of reporting. Radiation data were available for 81 patients. Twentyfour (30%) received craniospinal irradiation and 57 (70%) some form of local irradiation without spinal cord irradiation. Relapse patterns were only occasionally reported. Spinal seeding was reported in 7/39 (I 8%) patients. The radiation dose given for primary pineal region tumors of all types was usually in the range of 4500-5500 cGy ( 180200 cGy daily). No author reported routine use of lower radiation doses in verified germinomas. In this series, none of the 10 children treated with craniospinal irradiation relapsed, whereas two spinal relapses occurred among the remaining nine patients in whom the spine was not irradiated. The patients who received craniospinal irradiation were selected, in part, by an assumed increased risk of seeding. Eight of 19 (42%) patients were so categorized, using as adverse factors multiple intracranial tumor sites at diagnosis (4 patients), malignant cells in the CSF (2 patients), and diabetes insipidus (6 patients). Six (75%) of these patients received craniospinal irradiation. Two patients with diabetes insipidus alone were irradiated locally without subsequent relapse. In comparison 4/l 1 (36%) patients without any of these adverse factors underwent elective craniospinal irradiation and of the seven patients treated locally two relapsed in the spine. Additional variation in the use of elective craniospinal irradiation occurred due to uncertainty concerning the occult spinal seeding rate to be anticipated in patients undergoing biopsy with or without resection. Rates as high as 40% have been reported ( 17). Five patients were demonstrated to have multiple tumor sites or dissemination at diagnosis. None have relapsed. All but one (with thalamic involvement) received craniospinal irradiation. The involved regions received 5-5250 cGy and the electively irradiated component of the central nervous system received 2500, 3075, 3500, 4000 cGy, respectively. Two recent large series have provided strong evidence that craniospinal irradiation may not be necessary for most patients with verified pineal germinomas (12, 16). Lindstadt et al. reported on 13 patients with biopsy proven intracranial germinomas (all sites and ages). None relapsed
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after irradiation and only one received elective craniospinal irradiation. In addition 19 unbiopsied patients were treated without craniospinal irradiation and only one developed spinal metastases (12). Therefore. craniospinal irradiation was not recommended unless metastases were present at diagnosis, CSF cytology was malignant or gross tumor spill had occurred at tumor resection. Only I of 13 verified patients required craniospinal irradiation with these indications. Shibamato et al. reported on 70 patients with intracranial germinoma (all sites and ages). of which 42 were verified (histology 30 patients, cytology 12 patients) ( 16). The 5- and lo-year survival rates for verified cases were 84% and 76%, respectively. There was no significant difference in survival between patients treated with local as opposed to craniospinal irradiation, with 5year survival rates of approximately 77% and 84%, respectively, for verified patients and 9 1% and 87% for unverified cases. Results were not given for the patients who were less than 17-years old with pineal region germinomas, nor for verified and unverified patients by tumor site and irradiated volume. However. none of 12 patients (verified and unverified) with tumors in the pineal or pineal and suprasellar regions who received craniospinal irradiation relapsed, compared with 3/26 (12%) patients in whom the volume irradiated was less than the complete craniospinal axis. These authors favored elective craniospinal irradiation when there were multiple sites of tumor at diagnosis or when the CSF cytology was positive, that is. in about 60% of patients due to the very high CSF positivity rates in Japan. If craniospinal irradiation is undertaken selectively for patients with pineal region germinomas, with multiple tumor sites, metastatic seeding, malignant cytology, and diabetes insipidus as the indications, as is our present practice, this series forecasts that 8/ 19 (42%) of patients will be given craniospinal irradiation. In this series no patient with a verified germinoma relapsed in-field after irradiation. Therefore, the dose range of 44.5500 cGy was uniformly successful in tumor control. Included were six patients in whom the radiation dose range was 4-4500 cGy. Clearly. the optimal radiation dose is the lowest effective dose. A parallel might be drawn with germinomas in other locations, such as the testis. Testicular germinomas are successfully treated by irradiation at much lower doses. In the Toronto experience, patients with macroscopic regional spread of testicular germinoma (Stage 2A) treated with large volume irradiation in the dose range of 2-3000 cGy in 20-25 fractions had a 5-year survival rate of 87% ( 18). Low dose radiation was never used to treat unbiopsied pineal tumors, for it was recognized that the tumor mix at this site included some relatively radio-resistant tumors. The local control rate therefore increased with escalation of the radiation dose (17). The optimal radiation dose in verified pineal germinomas remains to be determined and this is an important objective for current pilot studies.
Pineal region germi nomas 0 D. JENKIN et (11.
None of the five unverified “germinomas” among the 2 1 patients reported, including three with dissemination at diagnosis, relapsed; this is excellent confirmation of the correctness of the clinical diagnosis. Significant morbidity occurred in the long-term survivors, mainly in relation to the central nervous system. It is difficult to distinguish damage done by the tumor, both directly and from prolonged raised intracranial pressure, and that due to surgical and radiation treatment. Morbidity due to the tumor can only be decreased by earlier diagnosis but treatment morbidity can be reduced by determining what is the least morbid, yet still effective, treatment and using such treatment. There are good grounds for believing that currently pineal germinomas are being over-treated. In this series it is uncertain whether partial or subtotal tumor resection of a pineal germinoma contributed towards local control, since all our verified patients achieved local control regardless of the extent of the surgical pro-
545
cedure. In uncomplicated patients it may be that small volume low dose local irradiation, in biopsied but not resected pineal germinomas, is just as effective as craniospinal irradiation, with a high dose boost to a large local volume, after tumor resection. This needs to be determined. Should elective chemotherapy be undertaken? We now know that chemotherapy can be curative for testicular germinomas, and that pineal germinomas respond well to similar drug regimens (2, 5). Such regimens are intense and have significant systemic toxicity. Children with pineal germinomas do not need elective combination chemotherapy to increase the cure rate. Pilot studies of combined modality therapy or chemotherapy alone will need to focus on the difficult end point of decreased morbidity, but these too are indicated. In summary, pineal germinomas in children are nearly always cured. It is necessary to determine the method which will achieve this objective with the least morbidity.
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