• Christina Stiverson

Novel Therapies, Trials, & The Future

Updated: May 19



As a parent of a child with rare pediatric cancer, most of us do not feel like we are in control of our child’s situation. Often lacking standard protocols, even experienced clinicians have to use judgement and sometimes ‘best guesses’ to navigate upfront treatment regimens. Sadly, in cases of unresponsive, metastatic, and relapsed patients, there is simply no roadmap for treatment and a feeling of desperation sets in for patients, families, & providers.

Hepatoblastoma is typically survivable, although many treatments cause long-term complications we are only beginning to study. This article is an attempt to inform parents and patients who are interested in what novel treatments are in development as of 2020. These treatments should provide hope for a limited population of those patients where frontline therapies have not been effective, and ultimately may prove worthy as an option for initial treatment if they can prove their safety and advantages over time.

DISCLAIMER: This is not intended to be medical advice! Although this article has been reviewed by providers, every child’s situation is unique. If you have interest in any of the novel therapies, or questions about how it may pertain to your child’s case, then please bring it up to your provider and/or ask for a second opinion.


Most families reading this probably have a baseline knowledge of how trial medicine works (if that is true then skip to the novel therapies section). However, if you want a refresher then here is a quick synopsis:


  • Lab scientists (including pathology, surgery, oncology, biology, etc.) study a patient population and attempt to identify a ‘target’ for which an existing or novel approach could theoretically make an impact on a disease community. Perhaps they will look at how the disease grows in place or moves (metastasizes) to a new area of the body. Ideally, the cancer can be attacked without affecting normal functions of the anatomy. Hepatoblastoma enjoys a small but very gifted group diving into better ways to attack the cancer and reduce the impact on children. They are studying the pathology of high-risk tumors, biological markers/signaling pathways of aggressive disease, and building models to study drug effects.


  • A trial is initiated with patients to identify the levels that the therapy can be administered without causing overly toxic & negative effects (Phase I). Once the toxic levels are known, the trial then moves on to understand what dose shows efficacy in fighting the cancer (Phase II), without going over the Phase I maximum (in rare cases, a drug is administered under special care above Phase I levels to achieve greater therapeutic effect). During follow-on portions, the drug can be studied in combination with other therapeutic techniques and optimized for effect and safety (Phase III). Ultimately (and usually after years of development) the therapy could be included in a Standard of Care and science can then move on to survivorship and other issues.


The narrative above seldomly holds true for rare pediatric cancer simply because the sample size of patients is far too small to follow the normal scientific method. One glaring difference is the placebo effect. . .giving some patients no treatment (a blind placebo) while measuring the difference on the population receiving the actual treatment. With deadly diseases in children, placebos are foregone, and we can’t clearly understand how effective treatments really are.


Where we stand today with Hepatoblastoma is continued progress of PHITT (Pediatric Hepatic International Tumor Trial), a brilliant collaboration covering hundreds of institutions from around the globe. This trial continues to morph, now splitting patients into additional ‘arms’ for the purpose of identifying distinct protocols depending on how patients present at diagnosis. PHITT is the best capture of what can be accomplished with upfront care, but it doesn’t account for many patients with relapse disease who “fall off the trial”.


NOVEL THERAPIES, TRIALS, AND THE FUTURE

Indocyanine Green (ICG) “Green Dye” Surgical Employment

In the last few years, doctors in Japan moved a decades old dye used in surgery into the Hepatoblastoma landscape. Taken prior to resection or transplant surgery, the dye bonds in a concentrated form to Hepatoblastoma tumors and then is revealed under special equipment for the surgeon. So far, ICG has highlighted previously undetected areas of disease but also could be showing “false positives”.


Dr Greg Tiao gave a powerful lecture on the potential of ICG at the recent international pediatric liver tumor conference sponsored by the Cincinnati Children’s Hospital. He was also very forthright about the fact that this procedure has not been subjected to proper study yet. His concerns lay not with the safety of the procedure, but with the lack of data substantiating its use. Despite this, there are efforts to more rigorously study this tool going forth. More Reading: ICG Dye “Lights up” Hepatoblastoma in the Lung that CT Scans May Miss



Radioembolization in High Risk Pediatric Liver Cancer

This technique is a cross-over therapy developed for other cancers. Radiation has not enjoyed much success against solid tumors like Hepatoblastoma. However, delivery of radioactive particles in a targeted fashion through arterial passages has achieved some promising effects with relatively low side effects.

TARE-Y90 of unresectable primary liver malignancy is both technically feasible and demonstrates an anticancer effect, and retreatment is well tolerated. TARE-Y90 could be considered as adjunctive therapy in pediatric patients with unresectable hepatic malignancies and could be used as a bridge to surgical resection or liver transplant. More research is required to determine the efficacy of this treatment in children and to define the clinical scenarios where benefit is likely to be optimized.-PubMed, 2019

More Reading: Radioembolization (TARE-Y90) for Liver Tumors

More Reading: Targeted, image-guided therapy offers an alternative for children with liver cancer



Radiofrequency Ablation as a Technique for Metastatic Disease

Radiofrequency ablation (RFA) is a minimally invasive treatment that involves using imaging (ultrasound, CT or MRI) to guide a needle electrode into a tumor. An electrical current is then passed through the electrode, heating and killing the cancer cells. RFA is often used in patients for whom surgical resection is not an option. Radiofrequency ablation works best on tumors that are less than 1.5 inches in diameter and is often used along with chemotherapy and radiation to shrink the tumor.-Emory Hospital

More Reading: Reiterative Radiofrequency Ablation in the Management of Pediatric Patients with Hepatoblastoma Metastases to the Lung, Liver, or Bone

More Reading: First Experience of Ultrasound-guided Percutaneous Ablation for Recurrent Hepatoblastoma after Liver Resection in Children



Evaluating GPC3-CAR T Cells for Children with Relapsed/Refractory Liver Tumors

A rapidly emerging immunotherapy approach is called adoptive cell transfer (ACT): collecting and using patients' own immune cells to treat their cancer. There are several types of ACT (TILs, TCRs, and CARs), but, thus far, the one that has advanced the furthest in clinical development is called CAR T-cell therapy. Until recently, the use of CAR T-cell therapy has been restricted to small clinical trials, largely in patients with advanced blood cancers. But these treatments have nevertheless captured the attention of researchers and the public alike because of the remarkable responses they have produced in some patients—both children and adults—for whom all other treatments had stopped working. –National Cancer Institute

Currently Texas Children’s Phase I research study is available to Hepatoblastoma patients, and a trial will begin soon using antibodies to GPC3 (a similar target used in the CAR-T study) for patients with Hepatoblastoma and other GPC3 expressing tumors. Expect locations at MSKCC, CCHMC, DFCI, and Emory. More Reading: CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers



Sodium Thiosulfate (STS) for Protection from Cisplatin-Induced Hearing Loss

For survivors of hepatoblastoma, the most common lasting treatment effect is hearing loss. As of May 2020, sodium thiosulfate (STS) has not yet received approval by the FDA as an otoprotectant, but it is anticipated that it will ultimately be approved for patients receiving cisplatin for localized hepatoblastoma, perhaps this year, and its use is already increasing in some parts of the world, including areas in the United States.


Data to support its use comes from the results of two large studies which demonstrated that STS can reduce the number of patients that develop severe hearing loss from cisplatin by approximately half, from 60% to 30% of patients. From the COG study, there is some debate over whether STS had a ‘tumor protective effect’, particularly in patients with metastatic disease, though in the SIOPEL (European) study, focusing on patients with localized hepatoblastoma, such tumor protective effect was not found. In its current form, the AHEP1531/PHITT trial now permits the use of STS for patients with localized hepatoblastoma.


It’s important to note that there is no data available to support the use of STS in patients receiving less than 6 cycles of therapy. Clinicians and parents are advised to consider the risks (theoretical protection of tumor from cisplatin) vs the benefit (lower rates of irreversible hearing loss) when recommending and considering the use of STS. STS must NOT be used for patients in Group D on the international trial (patients with metastatic hepatoblastoma), due to concern for potential tumor protection identified in study ACCL0431 in patients with metastatic disease.(The STS portion of this article was written by James Geller, MD, Director of the Liver and Renal Tumor Program at Cincinnati Children’s Hospital.)


Reference: Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss

Reference: Effects of Sodium Thiosulfate vs. Observation on Development of Cisplatin-Induced Hearing Loss



Final Notes

Dr. Allison O’Neill (Director, Solid Tumor Program and Liver Tumor Center, Dana-Farber Cancer Institute and Boston Children’s Hospital) has focused recent efforts on two analyses to better understand AFP kinetics and the prognostic significance of AFP decline and fluctuations in this tumor marker. The first study is focused on an analysis of AFP patterns from all patients (>100) treated on the COG AHEP0731 clinical trial.


The second analyses will study AFP values from >1000 patients treated on an international, retrospective database. As changes in AFP are a source of significant stress for families with children diagnosed with Hepatoblastoma, or other AFP secreting tumors, Dr. O’Neill is hoping to shed more light on the interpretation of changes in this laboratory value.


Also on deck--what else is next in the trial landscape? Dr Bruce Morland (Birmingham, Enlgand) is leading the international committee (in concert with the Children’s Oncology Group) to plan PHITT2, the PHITT successor trial. PHITT is quickly nearing the anticipated 1,500 patient enrollment and approximately half-way through its lifecycle.


There are several labs in the US and internationally which are investigating novel or translational approaches for those suffering from Hepatoblastoma. However, this article focused on those which are closest to impacting the community. If you are interested in pre-clinical research, please see the research portion of our site or contact us. In addition, if you have suggestions for procedures or ideas we missed—please reach out to us via connect@hepatoblastoma.org


By: Cody Stiverson, International Parent Liaison for The Hepatoblastoma Resource Network

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