1. Goodwin, Peter M.

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MILAN-Injections of inert hafnium nanoparticles into tumors doubled pathologic complete response rates to subsequent radiotherapy for patients with soft tissue sarcomas (STS) of limbs in comparison with patients having similar radiotherapy without prior hafnium injections. These findings from the Act.In.Sarc multinational phase II/III study were reported at the 2019 European Society for Radiotherapy and Oncology (ESTRO) conference (Abstract OC-0271).

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"Hafnium oxide nanoparticles are first-in-class radio-enhancers," said study co-author Juliette Thariat, MD, PhD, Professor of Radiation Oncology at the Centre Francois Baclesse in Caen, northern France. "We have proof of concept for a tumor type that was radio-resistant. We have very good tumor response without increased toxicity. This is very promising for many other tumor types."


Hafnium can enhance the effect of radiation because the large mass of each atom can absorb correspondingly large amounts of energy when irradiated. If such atoms are injected into tumor cells, they absorb far more energy from the radiotherapy than would be absorbed by the much lighter elements, which comprise most of the mass of the cancer cells. Thariat said this means that the nanoparticles can then release this energy more locally: precisely into the tumor, where it is needed to kill cancer cells.

Juliette Thariat, MD... - Click to enlarge in new windowJuliette Thariat, MD, PhD. Juliette Thariat, MD, PhD

"We injected the tumors of the patients who had sarcomas of the limbs or the soft tissues [for whom] we would have been afraid they would not be able to receive complete surgery. After one single injection [of] nanoparticles (later activated by the radiation), we would expect the efficacy of the radiation would increase and would make the safety margins of the resection larger."


Study Details

The phase II/III trial had a standard arm with patients who received preoperative radiation-50 Gray (GY) for 5 weeks-and then surgery a few weeks after. Those in the experimental arm had their radiation therapy preceded by an injection of hafnium oxide nanoparticles and then had the same surgical options.


A total of 180 patients with locally advanced STS of the extremity or trunk wall were randomized (with all patient and tumor characteristics well-balanced, apart from sex) to receive a single intratumoral hafnium oxide injection and radiotherapy, or radiotherapy alone followed by surgical resection. Pathologic complete response rate was the main endpoint of the trial because it was regarded as a good surrogate for local control and for achieving clear resection margins, Thariat explained.


"The first endpoint was met," she noted. "We doubled the pathological response rate from 7.9 to 16.1 percent, which is quite good-especially in sarcomas which are radio-resistant tumors. And this translated into better safe resection margin rates. We are [now] expecting the longer-term results."


Seventy-seven percent of patients treated with hafnium had clear surgical margins as compared with 64 percent of those in the control arm. The limb amputation rate was decreased by 50 percent in the experimental arm. The injections showed "very good local tolerance" without the need for modifying radiotherapy. The intratumoral injections caused pain in 12 patients and grade 3-4 acute immune reactions in seven. But these adverse events were reported as "of short duration, manageable, and, in some cases, resolved spontaneously."


The investigators concluded that both the primary and secondary endpoints were met with a safety profile that was similar in both arms. The authors also noted that hafnium before radiotherapy represented a "new preoperative treatment option for locally advanced STS."


Change Practice?

When asked if the study should change practice for soft tissue sarcoma, Thariat said it should. "Patients should probably receive the injection of nanoparticles before radiation." And the reassurance the technique brings about margin safety was also on her list of pluses.


"There should be a clinical benefit. We are still waiting for longer, more clinical endpoints to really answer that question. But the primary endpoint is already very good. There's a clear message that the trial was very positive," she said. And she thought the findings could have strong implications well beyond sarcoma.


"There are many other tumor settings where radio-enhancing nanoparticles would be interesting," Thariat said. She considered head and neck cancer treatment, for example, could improve.


"Head and neck tumors are not that radio-resistant, but the risk benefit can be improved if you can increase the local dose effect without increasing the toxicity-which is a major issue in head and neck because we have 70 percent grade 3 or 4 toxicities (like mucositis) during the treatment and this sometimes prevents us from going up to the end of the treatment," she concluded.


Peter M. Goodwin is a contributing writer.