Pedmark Reduces Ototoxicity Risk in Cisplatin-Treated Pediatric Solid Tumors

Nilay Shah, MD

Sodium thiosulfate (Pedmark) has shown promise as an ototoxicity-mediating agent in pediatric patients with solid tumors treated with cisplatin, according to Nilay Shah, MD. He noted that additional research is needed to determine the long-term effects of this agent.

On September 20, 2022, the FDA approved sodium thiosulfate in pediatric patients aged at least 1 month who have localized, nonmetastatic solid tumors.¹ The agent has been proven to reduce the risk of ototoxicity associated with cisplatin, as evidenced in the randomized, open-label, multicenter phase 3 SIOPEL6 (NCT00652132) and phase 3 COG ACCL0431 (NCT00716976) trials.

The SIOPEL6 trial investigated cisplatin-based chemotherapy with or without sodium thiosulfate in patients between the ages of 1 month and 18 years with standard-risk hepatoblastoma. Investigators found that the incidence of hearing loss was lower in patients who received the combination compared with those who received cisplatin alone (39% vs 68%).

The COG ACCL0431 trial evaluated the efficacy of cisplatin-based chemotherapy with or without sodium thiosulfate in patients aged 1 to 18 years with newly diagnosed solid tumors such as germ cell tumors, hepatoblastoma, neuroblastoma, medulloblastoma, and osteosarcoma. Incidence of hearing loss was also lower in patients who received the combination in this trial, at 44% vs 58% in those who received cisplatin alone.

“There are clear patients in whom the use of sodium thiosulfate as a standard of care [SOC] should be considered, based on those most recent retrospective studies, including patients with localized tumors, particularly those who are young, under 6 years of age, and those who seem to be at the highest risk,” Shah said in an interview with OncLive^®.

In the interview, Shah, a physician scientist in the Center for Childhood Cancer and Blood Diseases at Nationwide Children’s Hospital and an assistant professor in the Department of Pediatrics at The Ohio State University College of Medicine, discussed the importance of this approval for pediatric patients with solid tumors, the favorable toxicity profile of the agent, and how these trial findings may inform future care in this population.

OncLive^®: Could you discuss the significance of the approval of sodium thiosulfate for the prevention of cisplatin-induced ototoxicity in pediatric solid tumors?

Shah: [Regarding current] treatments for pediatric solid tumors, many patients are receiving cisplatin as part of their curative therapy, and, in some cases, in later lines of therapy as well. With the advances that we’ve made across many solid tumors, the improvements in survival have been quite significant and dramatic, [in the range of] 30 to 40 years, but oftentimes, [these come] at the cost of treatment-related morbidity.

For many of our patients—especially those with tumors such as hepatoblastoma, medulloblastoma, and neuroblastoma—who are particularly young and receiving cisplatin, the risk of significant ototoxicity is dramatic. Some recent reviews and retrospective research have shown that rates can be as high as 65% in those patients.

The ability to obtain a drug which has good evidence and shows a reduction in that risk of ototoxicity can have a dramatic effect on the quality of life for these patients. Just because we’ve worked to cure them of their disease doesn’t mean that they should have to suffer the stigma of it for the rest of their lives.

The FDA approval [of sodium thiosulfate] makes it easier to have access to the agent for patients and families and should hopefully also better integrate the use of products like it into SOC treatment. [This approval] will make more physicians, pharmacies, and institutions aware of sodium thiosulfate as a toxicity-modifying drug, in the same way that, for patients receiving anthracyclines, we now routinely use dexrazoxane [Zinecard] to reduce [cardiotoxicity]. It’s a promising advancement that should make the holistic approach toward treating our patients a bit easier.

What is the mechanism of action of sodium thiosulfate?

Sodium thiosulfate works by acting as a scavenger for free radicals. Platinum agents, particularly cisplatin, work as an adduct to DNA and a crosslink to DNA, but this results in a significant release of inflammatory molecules, including reactive oxidative species. In the inner ear, that leads to direct damage to the cilia, and in humans, that damage is irreversible.

Sodium thiosulfate, when it’s infused, can enter that space in the inner ear and scavenge those free radicals, mitigating the degree of direct toxicity to the cilia and preventing premature damage. The timing of the sodium thiosulfate [administration], as a result, is important. When administered too close to either a preceding or subsequent dose of cisplatin, there’s potential for reduction of efficacy. There is a clear window of administration, which allows for otoprotection without reducing the efficacy of the chemotherapy.

What key efficacy data were found with the SIOPEL6 and COG ACCL0431 trials?

SIOPEL6 looked more at tumors like hepatoblastoma. [In that disease,] tumors tend to be restricted in their metastatic potential, although they can have widespread involvement of the liver, and occasionally some distant metastases. It was a cleaner study in that sense.

There was clear evidence that administration of sodium thiosulfate 6 hours after the completion of cisplatin infusion, and at least 10 hours before the subsequent dose, [caused] significant improvements in the rates of cisplatin-associated ototoxicity, without any direct effect on disease-free survival [DFS] or overall survival [OS]. Those data were quite impactful, and the analyses were robust.

The COG ACCL0431 study had 2 cohorts; this was more of a basket study. Any patients who were receiving a platinum agent, typically cisplatin, were eligible. Patients had hepatoblastoma, medulloblastoma, neuroblastoma, and osteosarcoma, predominantly, and some germ cell tumors were also included in those cohorts. [This study did not have] a pre-planned analysis based on the metastatic burden of the disease. The analyses were done post-hoc.

For patients with localized disease, there was excellent evidence showing reduction in ototoxicity over time with the use of sodium thiosulfate, without a significant effect on DFS or OS.

In the post-hoc analysis of the patients with metastatic disease, the results were a bit more controversial. This [trial] was done in a randomized fashion, where half of patients did not receive sodium thiosulfate and the other half did. Although there was a reduction in the ototoxicity in those patients receiving sodium thiosulfate, there were questions about its effects on survival. Because this was a post-hoc analysis from a basket study, there wasn’t sufficient stratification of patients to treated or untreated arms based on their disease histology. Ultimately, the data showed that patients who did not receive sodium thiosulfate seemed to have a higher event-free survival compared with patients who did receive sodium thiosulfate.

However, when looking at the historical data for expected outcomes in patients who had metastatic disease that was treated with cisplatin, the untreated, or control, arm on the study seems to have done exceedingly better than historical controls would have suggested. Because this was a post-hoc analysis, there were some questions regarding whether this was an accurate analysis. The interpretation from the original researchers introduced some of that question regarding the effect on survival for these metastatic patients. Was this a conclusion that could be clearly confirmed? There was some doubt there. There’s a recommendation for repeat studies to evaluate the effect on patients with metastatic disease in a more planned analysis.

Setting aside the information regarding the metastatic patients, the data from both studies, SIOPEL6 and COG ACCL0431, clearly demonstrated that you can treat patients with localized disease burden with sodium thiosulfate and decrease their risk of ototoxicity, while having no significant effect on disease-related survival.

What adverse effects should clinicians be aware of with this agent? Would any of these deter you from using this agent in certain patients?

The primary toxicity of sodium thiosulfate is related to the bolus of the actual sodium that’s part of the compounding. Usually, at the time of the infusion, [patients have] a sudden degree of nausea and/or vomiting. The patients can literally feel that sensation. [This is] interesting, in that which patients will feel that sensation and have significant nausea and vomiting is somewhat hard to predict. [This toxicity does seem to arise in more] older patients, those school-aged and adolescent patients, compared with infants, toddlers, and preschool- or early school–aged children.

Regardless, this is certainly a toxicity that can be directly managed. We recommend the administration of an antiemetic as a pre-medication to the administration of sodium thiosulfate. Generally, that can control the symptom. It is not an ongoing, prolonged nausea; it seems to be administration-specific and manageable. I would not recommend that physicians avoid the use of sodium thiosulfate [because of its toxicity] alone.

How do you see sodium thiosulfate fitting into the current treatment paradigm for this population?

Frankly, it should be considered for all patients who are going to be receiving multiple doses of cisplatin, including those with hepatoblastoma, medulloblastoma, osteosarcoma, and germ cell tumors. There are some questions regarding in which patients with neuroblastoma this will be most appropriate.

[However, in general, sodium thiosulfate is] worth discussing with patients who are potentially going to be receiving cisplatin, as well as other ototoxic agents, such as high-dose carboplatin. The indication for sodium thiosulfate is with the use of cisplatin. It should not necessarily be used in patients who are receiving high-dose carboplatin, but [it should be considered in patients] who will later be receiving high-dose carboplatin, because there’s an increased risk [of hearing loss with carboplatin, and the] use of sodium thiosulfate with cisplatin [earlier on] may reduce the overall risk of hearing loss.

The use of sodium thiosulfate should also be further investigated in a clinical trial capacity for some of those other cohorts, particularly in patients with metastatic disease. That’s a question within the research space.

What does the future look like for this agent?

Sodium thiosulfate needs to be further studied and considered in other contexts. Additionally, the introduction of sodium thiosulfate as a new adjunctive agent needs to [be a] whole-team [effort]. Since it is necessary to avoid overlap in the timing of the sodium thiosulfate with either preceding or subsequent doses of cisplatin, there will need to be some protocolization of the use of sodium thiosulfate in these patients. That will involve a comprehensive approach of partnering with nursing staff, pharmacy staff, nurse practitioners, and the rest of the medical team. Including all members in that conversation will help to demystify how the agent is meant to be used and how it can be best used.

I would also recommend that treating physicians reach out to collaborating partners who’ve had prior experiences with sodium thiosulfate to see how other institutions have made best use of the drug without causing much disturbance from a procedural standpoint.

What ongoing research at Nationwide Children’s Hospital would you like to note?

We are excited to be partnering through Children’s Oncology Group for future initiatives with sodium thiosulfate and other approaches to reduce ototoxicity. There’s much preclinical and clinical interest in this topic.

The other question that may arise [has to do with] not only the short-term and near long–term effects of these agents, but also the longitudinal effects. We clearly know that some patients are at risk for early hearing loss from the use of cisplatin, and that the use of drugs like sodium thiosulfate will mitigate that risk. However, we also know that [patients who receive] these agents on a long-term scale, 20, 30, or 40 years out, are at an increased risk for early hearing loss, as well as other hearing-associated toxicities such as tinnitus. That data hasn’t been collected yet. We look forward to partnering with our colleagues on many of these studies.

Reference

FDA Approves sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized, nonmetastatic solid tumors. News release. FDA. September 20, 2022. Accessed September 27, 2022. https://bit.ly/3BXm47E

Dr Shah would like to disclose that he has served on advisory panels for, and received a consulting remuneration from, Fennec Pharmaceuticals.