Treatment significantly reduces chemotherapy-induced hearing loss in children

Investigators from Children’s Hospital Los Angeles and 37 other Children’s Oncology Group hospitals in the U.S. and Canada have determined that sodium thiosulfate prevents cisplatin-induced hearing loss in children and adolescents with cancer. Results of this randomized, controlled, phase 3 study, called ACCL0431, have been published in the early online edition of Lancet Oncology.

This federally-funded, cooperative group study is the first to show that cisplatin-induced hearing loss can be reduced by about half in children and adolescents being treated for cancer,” said David R. Freyer, DO, MS, director of the Survivorship & Supportive Care Program in the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles, who was lead author and chair of the study. “It is an important step toward developing a safe and effective strategy that will greatly improve quality of life for cancer survivors.” Freyer is also professor of Clinical Pediatrics and Medicine at the Keck School of Medicine of USC.

Cisplatin is a chemotherapy medication widely used to treat a variety of cancers in both adults and children. Although effective, cisplatin frequently causes permanent hearing loss and tinnitus (ringing in the ears), resulting in functional disability for patients who receive it. For young children in particular, hearing loss is especially serious because it results in impaired language development, learning and social interactions. Preventing ototoxicity, while preserving chemotherapeutic efficacy, has been a long-standing goal of physicians, scientists, parents and survivors. Historically, there have been no proven treatments for preventing cisplatin-induced hearing loss tested under the rigorous conditions of ACCL0431. Without otoprotection, the only way to prevent hearing loss is to delete or decrease cisplatin doses, which could render the cancer treatment less effective.

In ACCL0431, 125 eligible participants between the ages of 1 to 18 years with newly-diagnosed cancer were enrolled over a 4 year period. The cancer diagnoses were hepatoblastoma, germ cell tumor, medulloblastoma, neuroblastoma, osteosarcoma, or other cancer types treated with cisplatin. Study participants were randomized to receive sodium thiosulfate or observation (control) during their chemotherapy. Their hearing was assessed at baseline, following completion of the chemotherapy regimen and 1 year later.

The investigators reported a significant reduction in the incidence of hearing loss in participants who were treated with cisplatin and sodium thiosulfate (29%) compared to those who received cisplatin alone (56%). The greatest benefit was seen in children younger than 5 years of age, who are most susceptible to, and also most affected by, cisplatin-induced hearing loss.

Other effects of sodium thiosulfate were carefully monitored in the study. Overall, sodium thiosulfate was tolerated well without any serious adverse events. Survival from the cancer was not affected by sodium thiosulfate among participants who had localized tumors. However, survival appeared to be lower among those with metastatic disease who received sodium thiosulfate. Additional research is needed to determine what role sodium thiosulfate should have in preventing hearing loss in specific subsets of patients being treated with cisplatin.

Freyer et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncology, 2016; DOI: 10.1016/S1470-2045(16)30625-8 [Abstract]

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Eye movement affected in former childhood cancer patients

Nowadays, the lives of the majority of all children with cancer can be spared. However, the cure for the disease comes with a price: some of the survivors will suffer long-term injury from the treatment. A study from Lund University in Sweden now shows that commonly used chemo toxins impair the eyesight in childhood cancer survivors in a way that indicates an impact on the central nervous system.

It was not the former patients’ visual acuity that had been damaged; rather their eye motor skills – the eyes’ ability to follow moving objects.”We observed that most of these patients were not able to move their eyes smoothly and steadily, but jerkily and fitfully. Eye movement like that makes it harder to focus on moving objects in traffic, for instance. It can also cause headaches and dizziness“, says reader Per-Anders Fransson at Otorhinolaryngology in Lund.

The study included 23 childhood cancer survivors, at the current age of 20 to 30, and compared them to 25 healthy people of the same age. Only a few in the first group experienced no visual disorders, headaches and dizziness. The degree of the problem appeared to be related to the degree of which the eye motor skills had been affected, which suggests damage to the central nervous system from the chemotherapy.

It has been previously known that cisplatin, methotrexate, and ifosfamide – the types of chemo which the subjects of the study had been treated with – can penetrate the so-called blood-brain barrier, and thereby damage the nervous system. What has not been known, however, is whether the eye motor skills could be affected, and the consequences of that.An average of 15 years had passed since the patients underwent cancer treatment. The study could not determine whether any of them had experienced side-effects which by now had worn off, but it’s clear that the majority of them are still suffering the effects of their treatment. Age, at the time of treatment, appears to play an important role: those who were youngest at the time of treatment were the most affected.

A child’s brain has not completely developed, which makes it more susceptible to the influence of foreign substances“, says Thomas Wiebe, consultant in paediatric oncology.

He argues that for the time being, despite the risks, we must continue to use the medicines in question – after all, curing the cancer and saving lives is most important. However, the Lund University study reinforces the importance of coming up with new and better treatments. In the future, the new knowledge, and the diagnostic method described in the study will enable oncologists to pay closer attention to any side-effects, in which case it may be possible to reduce the dosage or change medications.

Thomas Wiebe also finds that Swedish healthcare needs to focus more on the growing group of childhood cancer survivors. Only a third of them are completely free from side-effects, while the rest experience anything from mild to severe effects from their treatment.

Today, childhood cancer patients are monitored in paediatric clinics until they turn 18, but after that there is insufficient follow-up. We have introduced a ‘delayed effect clinic’ here in Lund, but it lacks sufficient resources, and the rest of the country has even less resources!“, he says.

Because the survivors of childhood cancer may experience problems not only with their balance and vision, but also with for instance cardiovascular diseases, fertility, growth and cognition, they presumably turn to various forms of care in search of help. If there was a good system for diagnosis and follow-up, they could receive the support they need right away.

When it comes to balance and visual disturbances, there is an exercise programme that can significantly minimise problems. Simply being diagnosed is also valuable so you don’t have to wonder why you are experiencing things such as dizziness and fainting“, says Professor of Otorhinolaryngology Måns Magnusson.

Einarsson et al. Oculomotor deficits after chemotherapy in childhood. PLoS ONE. 2016; 11(1): e0147703. doi:10.1371/journal.pone.0147703 [Article]

Survey sheds light on common clinical practice for incompletely resected lung cancer

A landmark survey of more than 700 specialists provides crucial real-world insight into the treatments most oncologists choose for lung cancer patients whose tumour has been incompletely resected, an expert from the European Society for Medical Oncology (ESMO) says.

Jean Yves Douillard, from the ICO Institut de Cancerologie de l’Ouest René Gauducheau, France, Chair of the ESMO Educational Committee, was commenting on a paper published in the journal Lung Cancer. In the study, researchers led by Raffaele Califano of The Christie NHS Foundation Trust, Manchester, UK, surveyed 768 oncologists from 41 European countries about the treatments they offered patients who had “R1 resected” non-small-cell lung cancer.

R1 resection is a term used by oncologists to indicate that it is possible to find microscopic evidence of cancer cells remaining after a cancer has been surgically removed.

We know that incomplete resection, or R1 resection, is associated with a higher risk of relapse but there are currently no strong evidence-based recommendations on how to treat these patients after surgery,” Douillard says.

This study is important since it provides a good overview on how the problem is handled in clinical practice all over Europe by practitioners who treat lung cancer.”

Overall, 83% of experts surveyed were medical oncologists –specialists trained to treat cancer using chemotherapy, targeted therapies, immunotherapy and other medications.

Of the respondents, 91.4% prescribed chemotherapy, mostly cisplatin/vinorelbine or cisplatin/gemcitabine. The survey showed that the majority of doctors (85%) discussed with the patient the fact that there was limited clinical evidence to guide treatment options. Almost 50% of participants prescribed radiotherapy, with radiation oncologists most likely to offer this treatment approach.

Treating physicians clearly believe in what they do, and try to provide the best for their patients,” says Douillard. “According to the survey, however, practice is heterogeneous and varies according to the specialty of the treating physician—whether they are radiation oncologists or medical oncologists. This is why treatment decisions are best made by multidisciplinary teams.”

The evidence gathered in this survey is supported by the recommendations of the 2nd ESMO Consensus Conference on Lung Cancer held in 2013, Douillard notes. That group of worldwide recognised experts recommended adjuvant chemotherapy and adjuvant radiation in R1 resected patients.

The authors of the latest paper call for prospective trials to be undertaken to provide stronger evidence to guide post-surgery treatment in this situation. Douillard agrees that such trials would be informative.

However, trials of adjuvant treatment in R1 resected lung cancer would be very difficult to design and perform, as this is fortunately an infrequent occurrence. R1 resection would also need to be clearly defined in such studies, as it actually represents a quite heterogeneous group.”

Based on evidence from clinical trials in resected patients in whom all tumour cells have been completely removed, there is a rationale for using both chemotherapy and radiotherapy in R1-resected non-small-cell lung cancer,” Douillard says.

As the authors of this survey state, definitive proof would come from a randomised clinical trial, although such studies would be difficult to perform.”

Additional Information:

Califano et al., (2014). Use of adjuvant chemotherapy (CT) and radiotherapy (RT) in incompletely resected (R1) early stage Non-Small Cell Lung Cancer (NSCLC): A European survey conducted by the European Society for Medical Oncology (ESMO) Young Oncologists Committee. Lung Cancer85(1):74–80 [Abstract][pdf]