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Adjuvant Chemotherapy for Ependymoma: Is It Necessary for All Children Under Five Years of Age?

University of Iowa College of Medicine, Iowa City, IA

To the Editor:We read with great interest the article entitled "Postoperative Chemotherapy Without Irradiation for Ependymoma in Children Under 5 Years of Age: A Multicenter Trial of the French Society of Pediatric Oncology" by Grill et al published in the March 1, 2001, issue of the Journal of Clinical Oncology.¹ In the abstract, the authors conclude, "a significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy." The conclusion of this abstract and article gives an impression that chemotherapy can be used so that irradiation can be avoided. In their study, the authors documented that 40% and 23% of children were spared from radiotherapy at 2 and 4 years, respectively, from the initiation of chemotherapy. The real question in this study is whether the same patients who were not irradiated could also have been spared chemotherapy. There is increasing evidence from the literature that in imaging-verified total resections, surgery alone may suffice. We would like to know the proportion of patients according to location and imaging-verified residual disease who did not receive radiotherapy. In a study by Hukin et al,² seven of 10 patients with radiographically confirmed gross total resection who were not given adjuvant radiotherapy or chemotherapy remained free of disease at a median follow-up of 48 months. In a study from our own institution,³ five patients (three adults and two children) with infratentorial tumors received no further adjuvant treatment after imaging-verified gross total resection. Four did not have recurrence of disease, with follow-up times ranging from 66 to 127 months.

Another interesting observation in this study is the unusually high proportion of high-grade tumors. Most institutional series report a higher proportion of low-grade tumors. The grade probably does not matter, as there is difficulty among individual pathologists as to grading and classification of ependymomas. In one multi-institutional study,⁴ diagnosis was discordant in 22 (69%) of 32 cases among institutional pathologists and central pathology reviewers.

Chemotherapy may be most useful only in the subset of children who have had imaging-verified residual disease. The fact that 23% of patients at 4 years did not receive radiotherapy may not be a testimony to the efficacy of chemotherapy, but it may be due to the fact that these patients had imaging-verified gross total resection.

REFERENCES

1. Grill J, Le Deley M-C, Gambarelli D, et al: Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: A multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol 19: 1288-1296, 2001[Abstract/Free Full Text]

2. Hukin J, Epstein F, Lefton D, et al: Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29: 40-45, 1998[Medline]

3. Paulino AC: The local field in infratentorial ependymoma: Does the entire posterior fossa need to be treated? Int J Radiat Oncol Biol Phys 49: 757-761, 2001[Medline]

4. Robertson PL, Zeltzer PM, Boyett JM, et al: Survival and prognostic factors following radiation therapy and chemotherapy for ependymomas in children: A report of the Children’s Cancer Group. J Neurosurg 88: 695-703, 1998[Medline]

Response

Institut Gustav Roussy, Villejuif, France

In Reply:We thank Drs Paulino and Buatti for their comments on our article.¹ Their remarks fuel the controversy over the usefulness of adjuvant treatment in children with ependymoma. Our data show unequivocally that irradiation can be delayed until a possible relapse in children with complete resection confirmed by an early postoperative computed tomography (CT) or magnetic resonance imaging (MRI) scan. With this approach, approximately one fourth of the patients did not receive any radiation treatment at all, and in patients who required irradiation, this treatment was deferred for a median period of 11/2 years. These are the most important messages we want to get across to clinicians.

Paulino and Buatti raised the question of the need for adjuvant chemotherapy in all of these patients. We stated in the article that no radiologic response to adjuvant chemotherapy could be documented in children with a postoperative residue. As this type of chemotherapy was unable to control macroscopic disease, did it really control microscopic disease, or was chemotherapy unnecessary for these children, as stated by Paulino and Buatti? We think that our data cannot resolve these questions. However, given our results and the data from small series in the literature in which patients with ependymoma were cured by surgery alone, a randomized study could be proposed comparing adjuvant chemotherapy to no chemotherapy in children with totally resected ependymomas. However, a lot of children in whom initial resection was complete (verified by early postoperative imaging, and whatever the initial tumor site) did relapse, and this would argue against such a randomized trial with no adjuvant treatment in one arm.

In our study, 13 children had a supratentorial ependymoma (one low-grade and 12 high-grade tumors). Seven had a complete resection confirmed by early imaging. Five of these seven patients relapsed 9 to 42 months after the initiation of chemotherapy and received irradiation as part of the salvage therapy. At the last follow-up visit, five out of the seven children were alive in complete remission (CR) (two in CR1 and three in CR2) 21 to 87 months after the initiation of chemotherapy. Sixty children had an infratentorial ependymoma. Thirty-seven had a complete resection that was confirmed by early imaging. Twenty-five of the thirty-seven children developed a recurrence 5 to 45 months after the initiation of chemotherapy and received irradiation as part of their salvage regimen. At the last follow-up visit, 20 were alive in CR (12 in CR1 and eight in CR2) 9 to 89 months after the initiation of chemotherapy.

The fact that more than 60% of children with a radiologically confirmed complete resection developed a recurrence despite adjuvant chemotherapy probably signifies that more efficient adjuvant treatment is needed. If we want to spare these children the deleterious effects of irradiation at a young age, we must develop more effective chemotherapy.

In conclusion, we think that we should try to better define the proportion of patients who did not relapse after initial complete resection. Once these patients are accurately defined, the question of the usefulness of adjuvant treatment could be examined in this subset of patients. A better adjuvant chemotherapy protocol has to be found for patients at risk of relapse despite initial complete resection.

The high proportion of high-grade tumors in our series may reflect a referral bias, because only children sent to the medical oncologist for adjuvant treatment were eligible for the trial. In the case of completely resected low-grade tumors, the neurosurgeons may have chosen a wait-and-see policy. On the other hand, as mentioned by Paulino and Buatti, grading may vary between the pathologists in the absence of clearly defined and reproducible grading procedures. We have tried to avoid this problem by applying a systematic central review of the slides for histologic diagnosis and grading.

It is obvious that adjuvant treatment may be useful for children with incomplete initial resection. However, the Baby French Society of Pediatric Oncology regimen is not sufficiently potent for these patients, since all the children with a residuum progressed during follow-up. At present, we cannot definitively state that all children with radiologically confirmed complete resection require adjuvant treatment, but most of them do. Again, the main message in our study is that the irradiation can be deferred and in some cases avoided in children with imaging-verified initial complete resection. Is this mild adjuvant chemotherapy the price all children have to pay? This may not be the case, but probably only a fraction of them can be cured with surgery alone.

REFERENCES

1. Grill J, Le Deley M-C, Gambarelli D, et al: Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: A multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol 19: 1288-1296, 2001

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Paulino, A. C. Articles by Kalifa, C. Search for Related Content PubMed PubMed Citation Articles by Paulino, A. C. Articles by Kalifa, C. Social Bookmarking                            What's this?