Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.
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Thompson Eric M, Hielscher Thomas, Bouffet Eric, Remke Marc, Luu Betty, Gururangan Sridharan, McLendon Roger E, Bigner Darell D, Lipp Eric S, Perreault Sebastien, Cho Yoon-Jae, Grant Gerald, Kim Seung-Ki, Lee Ji Yeoun, Rao Amulya A Nageswara, Giannini Caterina, Li Kay Ka Wai, Ng Ho-Keung, Yao Yu, Kumabe Toshihiro, Tominaga Teiji, Grajkowska Wieslawa A, Perek-Polnik Marta, Low David C Y, Seow Wan Tew, Chang Kenneth T E, Mora Jaume, Pollack Ian F, Hamilton Ronald L, Leary Sarah, Moore Andrew S, Ingram Wendy J, Hallahan Andrew R, Jouvet Anne, Fèvre-Montange Michelle, Vasiljevic Alexandre, Faure-Conter Cecile, Shofuda Tomoko, Kagawa Naoki, Hashimoto Naoya, Jabado Nada, Weil Alexander G, Gayden Tenzin, Wataya Takafumi, Shalaby Tarek, Grotzer Michael, Zitterbart Karel, Sterba Jaroslav, Kren Leos, Hortobágyi Tibor, Klekner Almos, László Bognár, Pócza Tímea, Hauser Peter, Schüller Ulrich, Jung Shin, Jang Woo-Youl, French Pim J, Kros Johan M, van Veelen Marie-Lise C, Massimi Luca, Leonard Jeffrey R, Rubin Joshua B, Vibhakar Rajeev, Chambless Lola B, Cooper Michael K, Thompson Reid C, Faria Claudia C, Carvalho Alice, Nunes Sofia, Pimentel José, Fan Xing, Muraszko Karin M, López-Aguilar Enrique, Lyden David, Garzia Livia, Shih David J H, Kijima Noriyuki, Schneider Christian, Adamski Jennifer, Northcott Paul A, Kool Marcel, Jones David T W, Chan Jennifer A, Nikolic Ana, Garre Maria Luisa, Van Meir Erwin G, Osuka Satoru, Olson Jeffrey J, Jahangiri Arman, Castro Brandyn A, Gupta Nalin, Weiss William A, Moxon-Emre Iska, Mabbott Donald J, Lassaletta Alvaro, Hawkins Cynthia E, Tabori Uri, Drake James, Kulkarni Abhaya, Dirks Peter, Rutka James T, Korshunov Andrey, Pfister Stefan M, Packer Roger J, Ramaswamy Vijay, Taylor Michael D
Аннотация
METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival.
FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084).
INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection.
FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.