FLASH radiotherapy has become one of the most closely watched areas in radiation oncology because of its potential to spare normal tissues while maintaining anti-tumor activity.
A first-in-human phase I dose-escalation study, the IMPulse trial, now provides early clinical safety data for FLASH radiotherapy in patients with cutaneous metastases from melanoma.
The study, published in Radiotherapy and Oncology, evaluated single-fraction FLASH radiotherapy in patients with progressive melanoma skin metastases refractory to systemic treatment.
The findings suggest that FLASH radiotherapy delivered up to 28 Gy in a single fraction was generally well tolerated in small-volume cutaneous lesions, with no dose-limiting toxicities observed during the predefined 4-week surveillance period.
Why This Study Matters
FLASH radiotherapy delivers radiation at ultra-high dose rates within milliseconds, compared with minutes for conventional radiotherapy.
Preclinical studies have suggested that FLASH radiotherapy may reduce normal tissue damage while preserving anti-tumor effects. This phenomenon, often called the FLASH effect, could potentially widen the therapeutic window of radiotherapy.
However, clinical translation remains early.
Until now, human data have been limited, partly because FLASH-capable treatment systems are not widely available and because safe dose levels need to be defined carefully.
The IMPulse trial was designed to test whether escalating single-fraction doses of FLASH radiotherapy could be delivered safely in patients with superficial melanoma metastases.
Study Design
IMPulse was a unicenter phase I dose-escalation trial conducted at Lausanne University Hospital.
The trial enrolled patients with metastatic melanoma and progressive cutaneous metastases despite systemic treatment.
A classical 3 plus 3 dose-escalation design was used.
FLASH radiotherapy started at 22 Gy in a single fraction and increased in 2 Gy steps, with planned escalation up to 34 Gy.
Dose-limiting toxicity was defined as any grade 3 or higher adverse event occurring in the irradiated field within 4 weeks after treatment.
The primary objective was to determine the maximum tolerated dose.
Secondary endpoints included tumor response, late side effects, and blinded central review of in-field skin reactions.
Treatment Approach
FLASH radiotherapy was delivered using a 9 MeV Mobetron electron beam system.
The dose rate exceeded 200 Gy per second, and treatment was delivered in 10 pulses over 90 milliseconds.
This very short delivery time is one of the defining features of FLASH radiotherapy.
Because the system used electron beams with limited penetration depth, the trial focused on superficial lesions. Treated metastases had to be cutaneous, limited in size, and located outside previously irradiated areas.
Dosimetry was performed using alanine, thermoluminescent dosimeters, and film-based measurements.
Patient Population
Between June 2021 and September 2024, 11 patients were enrolled.
Ten patients were ultimately treated, and 15 melanoma skin metastases received FLASH radiotherapy.
One patient was enrolled at two separate dose levels for different lesions.
All patients had metastatic melanoma with progressive cutaneous disease despite systemic therapies.
Most treated lesions were small-volume metastases. One large-volume lesion was treated at 22 Gy, but the large-volume cohort could not be completed because of limited recruitment.
The trial was discontinued after completion of the 28 Gy dose level because of slow accrual.
Dose Escalation and Safety
Dose levels of 22 Gy, 24 Gy, 26 Gy, and 28 Gy were completed in the small-volume cohort.
No dose-limiting toxicities were observed during the 4-week surveillance period at any administered dose level.
As a result, the maximum tolerated dose was not reached up to 28 Gy.
Most in-field toxicities were grade 0 to 1, with some grade 2 skin events.
At 28 Gy, one delayed grade 3 radiation-induced epithelitis occurred at week 6, outside the predefined dose-limiting toxicity window. This event was scored as grade 2 by blinded imaging central review and was healing at last follow-up.
The trial also reported serious out-of-field adverse events, including hepatic failure, dyspnea, melanoma progression, and assisted suicide, but none were attributed to FLASH radiotherapy.
Skin Toxicity Assessment
The study used both investigator assessment and blinded imaging central review.
Blinded review was generally consistent with investigator assessment, although the highest toxicity grade by blinded review was grade 2.
Across all dose levels, there was no clear increase in the frequency or severity of in-field skin adverse events as the FLASH dose increased from 22 Gy to 28 Gy.
This is an important observation, although the small sample size prevents firm conclusions.
The figure in the paper illustrates peak skin reactions after single-fraction FLASH radiotherapy at each dose level, including 22 Gy, 24 Gy, 26 Gy, and 28 Gy.
Tumor Response
Tumor response was encouraging in the treated lesions.
Across the 15 treated lesions, the investigators observed one complete response, 12 partial responses, and two cases of stable disease.
No treated lesion showed in-field progression.
The overall response rate was 100% at most dose levels, except at 24 Gy, where the response rate was 60%.
These response findings are exploratory, but they support continued evaluation of FLASH radiotherapy in superficial tumors.
Optical Coherence Tomography Findings
The trial also used optical coherence tomography to assess skin morphology after FLASH radiotherapy.
The OCT findings suggested progressive recovery of skin parameters after treatment.
Epidermal roughness, vascular plexus depth, vascular density, and vascular size showed changes at baseline related to the presence of metastases and inflammation, then moved closer to physiological values after treatment.
The authors interpreted these findings as consistent with elimination of the metastasis and good tolerance of the irradiated skin.
No clear dose-dependent OCT profile was observed across the tested FLASH dose levels.
Clinical Interpretation
The IMPulse trial provides an important early clinical signal.
Single-fraction FLASH radiotherapy up to 28 Gy was delivered without dose-limiting toxicity during the predefined acute observation window.
This is notable because single doses of 24 Gy or higher are generally considered beyond usual skin tolerance in conventional radiotherapy.
The findings are compatible with the possibility of normal tissue sparing at ultra-high dose rates, but the trial cannot prove the FLASH effect because it did not include a conventional radiotherapy control arm.
The study should therefore be interpreted as an early safety and feasibility trial rather than definitive evidence of superiority.
Limitations
Several limitations are important.
The trial was stopped early because of slow recruitment, so the planned dose escalation up to 34 Gy was not completed.
Only 11 patients were enrolled, and 15 lesions were treated.
Most lesions were small-volume cutaneous metastases, so the results cannot be generalized to larger tumors or deeper targets.
The median overall survival was short because patients had advanced melanoma with high tumor burden and progression after systemic therapy.
This limited the ability to assess late toxicity.
The absence of a conventional radiotherapy control arm also prevents direct comparison of acute or late skin effects.
Clinical Takeaway
The IMPulse trial is the first human dose-escalation study of FLASH radiotherapy.
In patients with cutaneous melanoma metastases, single-fraction FLASH radiotherapy up to 28 Gy did not produce dose-limiting toxicity within the 4-week surveillance period, and the maximum tolerated dose was not reached.
Early tumor responses were observed, with no in-field progression among treated lesions.
The findings are encouraging, but they remain preliminary.
Further studies are needed to define late toxicity, evaluate larger treatment volumes, compare FLASH radiotherapy with conventional radiotherapy, and determine whether the FLASH effect can meaningfully improve the therapeutic window in clinical practice.
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