Vincristine/irinotecan/temsirolimus upfront window treatment of high‐risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 Study Committee

Abstract

Background Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high‐risk (HR)/metastatic HB. Procedures Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha‐fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1–5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log10 decline) AFP decline after two cycles. Responders received two additional cycles of VIT intermixed with six cycles of cisplatin/doxorubicin/5‐fluorouracil/vincristine (C5VD). Nonresponders received six cycles of C5VD alone. Results Thirty‐six eligible patients enrolled on study. The median age at enrollment was 27 months (range: 7–170). Seventeen of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/mL and the median AFP following two VIT cycles was 19,262 ng/mL. Three‐year event‐free survival was 47% (95% confidence interval [CI]: 30%–62%), while overall survival was 67% (95% CI: 49%–80%). Conclusion VIT did not achieve the study efficacy endpoint. Temsirolimus does not improve the response rate seen in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen explored in this study. Additionally, AFP response may be a more sensitive predictor of disease response than RECIST in HB.

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“…While not powered to study outcomes, results from this stratum demonstrated that VI is an effective anti‐tumor combination for patients with advanced disease 18 . Addition of temsirolimus to the VI window (VIT) did not further improve response rates 30 . It is recognized now, in hindsight, that tumors associated with a low AFP level at diagnosis were likely rhabdoid tumors as “low AFP‐secreting HB tumors” are exceedingly rare in current HB trials and often reflective of small tumor size 31 .…”

“…18 Addition of temsirolimus to the VI window (VIT) did not further improve response rates. 30 It is recognized now, in hindsight, that tumors associated with a low AFP level at diagnosis were likely rhabdoid tumors as "low AFP-secreting HB tumors" are exceedingly rare in current HB trials and often reflective of small tumor size. 31 Patients with small cell undifferentiated (SCU) histologic features, of any proportion, were restricted to stratum 3 if fully resected, given that this histologic feature was felt to confer a poor prognosis.…”