UPDATE 3/27/2008: STS is now available on study. See: Children's Oncology Group Study, "A Randomized Phase III Study of Sodium Thiosulfate for the Prevention of Cisplatin-Induced Ototoxicity in Children (ACCL0431),"
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An interesting article was recently published in the January 15, 2008 edition of Clinical Cancer Research. The article, “Sodium Thiosulfate Administered Six Hours after Cisplatin Does Not Compromise Antineuroblastoma Activity”(1), points to new discoveries about a drug which could potentially protect our children's hearing from the devastating effects of therapy.
Over the years many articles have been published on hearing loss in children being treated for neuroblastoma. The reason for this is the common use of ototoxic drugs. Ototoxicity is damage to the ear, specifically the cochlea or auditory nerve, which is often associated with medications that are commonly used to treat neuroblastoma. These include the platinum compound chemotherapeutic medications, Cisplatin and Carboplatin, and the aminoglycoside antibiotics. These antibiotics are commonly used for treating gram negative bacterial infections which are, unfortunately, fairly common for children being treated for neuroblastoma. These drugs are the reason that so many children treated on the high risk protocols end up with significant hearing loss. It is a statistic that we often do not want to hear but 82% of children treated for neuroblastoma with Cisplatin during induction and Carboplatin for autologous stem cell transplant suffer from hearing loss(2).
Platinum-based drugs are associated with bilateral, progressive, sensorineural, irreversible hearing loss. The official documentation states that ototoxicity due to Cisplatin is characterized by outer hair cell degeneration in the basal turns of the cochlea, whereas ototoxicity due to Carboplatin is associated with the loss of inner hair cells (3) and is generally less severe and less frequent than Cisplatin-induced ototoxicity. Ototoxicity is the dose-limiting toxicity for Cisplatin and is associated with early, higher frequency hearing loss (>6,000 Hz) that progresses with higher cumulative doses to the impairment of lower frequency hearing (500-2,000 Hz; refs.4,5,6,7). Studies of Cisplatin associated hearing loss have found no evidence of recovery of hearing up to 4 years post treatment (4, 5, 7), and one recent study reported continuous worsening of hearing loss with time after completion of Cisplatin therapy (8). This is bad news for our children, for sure.
For obvious reasons, we need alternatives to help prevent hearing loss. Several drugs have been tested to help prevent ototoxicity. While some have shown to have a protective effect on hearing, the major problem seems to be that they also have the unfortunate side effect of protecting the tumor from chemotherapy. On some occasions there has even been speculation that these agents could help promote drug resistance in neuroblastoma. This is reason enough to be concerned about taking any drug that might prevent hearing loss.
Enter Sodium Thiosulfate (STS). Of all things, STS has been used for years as an antidote for cyanide poisoning. It has also been studied fairly extensively in guinea pigs, rats and Petri dishes. In fact, STS has been looked at for over 10 years in the cancer research literature for its hearing protective properties. In the last two years there has even been a human trial for children with brain tumors. The good news is that research clearly shows that STS is effective at protecting hearing from the ototoxic effects of the platin chemotherapies. The fear has always been that STS would also affect the neuroblastoma killing instinct of Cisplatin. In fact, they have shown that when they give STS along with Cisplatin this is exactly what happens. STS essentially wipes out Cisplatin’s ability to kill neuroblastoma cells. However, the interesting thing about this article is that they have found that, if they delay the administration of STS for 6 hours after the Cisplatin, they are able to not only preserve the neuroblastoma killing activity of Cisplatin but they are also able to protect hearing from the devastating effects of the drugs.
Now, for those of you who have hung around long enough, here is the technical stuff. In animal models, the delayed administration of STS until 2 to 8 hours after Cisplatin reduced Cisplatin-induced auditory damage (9,10). Delayed administration of STS to 6 hours after Cisplatin, given daily for 4 days as in the upcoming Children’s Oncology Group high-risk neuroblastoma study, did not affect the anti-tumor activity of Cisplatin in a subcutaneous neuroblastoma rat xenograft model. In addition, STS delayed to 6 hours did not diminish the in vitro cytotoxicity of Cisplatin, Carboplatin, or Etoposide in neuroblastoma cell lines (1). This article suggests that the use of STS 6 hours after Cisplatin for otoprotection is unlikely to compromise the anti-neuroblastoma activity of Cisplatin or Etoposide. Taken together with previously reported results in a rat model showing that STS given after Cisplatin can protect from ototoxicity (9), that there was a trend for improved protection from ototoxicity in children who received STS delayed to 4 hours (11), the in vitro and in vivo studies presented here support conducting a clinical trial to evaluate the delayed administration of STS as an otoprotective agent in high-risk neuroblastoma patients.
By now you probably understand that there is very often a rub when it comes to research. So, it is important to ask the question: Why isn’t this drug flowing into our kids? Why isn’t every child diagnosed with neuroblastoma being given this drug right now? The answer is simple. Even with all of this research the experts don’t know that that providing STS to real, live children with neuroblastoma after Cisplatin won’t have harmful effects that may even protect the tumor. Don’t get me wrong, this latest article does go along way in helping to answer this question. But the question still does remain and we don’t know if this will first “do no harm.” It has to be tested. After all, as much as we want to have our children hear after they finish therapy, we want them here after they finish therapy. We want them to be survivors.
The second barrier to getting this drug into our kids is priority. Research is give and take. There are limited funds and limited patients. Focusing on this research will come at the cost of another promising research question. Do we focus on preventing ototoxicity or do we focus on another drug that could potentially be the cure for neuroblastoma? The fact is that, by committing funds to this, something else will not be funded. Additionally, by making this trial available in upfront therapy, it will keep another therapy from being tested in that same therapeutic window right now. What is more important to you? As much as the medical community would probably disagree, this choice is probably up to us. We have the power to help direct research. Our dollars carry weight but it is our children that are the real capital. Is this where we spend our financial resources and our patient numbers? Is it important to you? What do you think?
Will we be hearing less about hearing loss?
1 Harned TM, Kalous O, Neuwelt A, Loera J, Ji L, Iovine P, Sposto R, Neuwelt EA, Reynolds CP Sodium Thiosulfate Administered Six Hours after Cisplatin Does Not Compromise Antineuroblastoma Activity. Clin Cancer Res 2008;537 14(2):533-40.
2 Simon T, Hero B, Dupuis W, Selle B, Berthold F. The incidence of hearing impairment after successful treatment of neuroblastoma. Klin Padiatr 2002;214:149_52.
3 Muldoon LL, Pagel MA, Kroll RA, et al. Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. Clin Cancer Res 2000;6:309-15.
4 Skinner R. Preventing platinum-induced ototoxicity in children-is there a potential role for sodium thiosulfate? Pediatr Blood Cancer 2005;47:120-2.
5 Schell MJ, McHaney VA, Green AA, et al. Hearing loss in children and young adults receiving Cisplatin with or without prior cranial irradiation. J Clin Oncol 1989;7:754-60.
6 Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J. Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol 1991;19:295-300.
7 Skinner R, Pearson AD, Amineddine HA, Mathias DB, Craft AW. Ototoxicity of cisplatinum in children and adolescents. BrJCancer 1990;61:927-31.
8 Bertolini P, Lassalle M, Mercier G, et al. Platinum compound-related ototoxicity in children: long-term follow-up reveals continuous worsening of hearing loss. J Pediatr Hematol Oncol 2004;26:649-55.
9 Dickey DT, Wu YJ, Muldoon LL, Neuwelt EA. Protection against Cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J Pharmacol ExpTher 2005;314:1052-8.
10 Muldoon LL, Pagel MA, Kroll RA, et al. Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. Clin Cancer Res 2000;6:309-15.
11 Neuwelt EA, Gilmer-Knight K, Lacy C, et al.Toxicity profile of delayed high dose sodium thiosulfate in children treated with Carboplatin in conjunction with blood-brain-barrier disruption. Pediatr Blood Cancer 2006;47:174-82.