A pioneering phase II clinical study on tri-modality therapy (START-FIT) has found that nearly 50% of patients with inoperable locally advanced liver cancer, can be cured through this innovative approach.
Liver cancer is the sixth most common cancer globally with more than 900 000 new cases every year and is the third leading cause of cancer-related mortality. The Hong Kong Cancer Registry reflects about 1 800 new cases every year.
However, only 30% of these are eligible for curative treatment, while the rest could solely be managed with non-curative option due to large tumour size, or vascular invasion etc. The research team focused on these 70% inoperable cases and developed a new treatment modality to improve their chance of cure.
A total of 33 patients were screened and enrolled in this treatment method from March 2019 to January 2021, for tumour diameter ranging from 5cm to 17.5cm. A total of 64% of the patients had tumours with major vascular invasion that precluded them from curative surgical procedure.
The study was conducted by the Department of Surgery and Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine of the University of Hong Kong (HKUMed).
The research team developed a new approach termed “Reduce and Remove” – a tri-modality therapy (START-FIT) for these 33 patients. Patients would receive Transarterial Chemoembolisation (TACE) on day one for local tumour control, followed by Stereotactic Body Radiation Therapy (SBRT) on day 28, and then immunotherapy administered 14 days following SBRT and every two weeks thereafter.
In brief, this tri-modality approach is to downstage the tumour status to a level amenable to surgical intervention to achieve a cure for the cancer.
After this novel tri-modality therapy, 55% (18 patients) became suitable to receive curative surgery, of whom four (12%) had undergone operation, and 14 patients (42%) had complete necrotic tumours who chose to keep close monitoring with regular scans. After up to 2.5 years of follow-up, two-year survival among these patients exceeded 90%, with only mild side-effects experienced throughout the whole treatment process.
The advantages of this approach are that it is minimally invasive with a short hospital stay and a relatively high safety profile. The most common side effects include temporary liver function derangement after TACE, and few patients may develop some mild immune-related reactions.
This innovative treatment strategy provides an opportunity for patients, who were initially not suitable, to eventually receive curative surgery with a promising long-term outcome.
“This treatment strategy provides a definite treatment schedule. Most patients could have (a better) idea of the treatment effect within six months after the start of treatment and be able to have better planning for themselves and their family," said Professor Albert Chan Chi-yan, clinical professor, Department of Surgery, School of Clinical Medicine, HKUMed, who initiated this global first novel tri-modality therapy.
“Now the team plans to expanding the treatment coverage to more patients, especially those with poor liver function, to help downstage the tumour status and increase the chance of fitting into the criteria for liver transplantation in the future. We are also seeking ways to improve the efficacy of immunotherapy, from single agent to double agents, to deliver a more enhanced and solid treatment result.”
Study details
Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial
Chi Leung Chiang, Keith Wan Hang Chiu, Kenneth Sik Kwan Chan, Francis Ann Shing Lee, James Chun Bong Li, Catherine Wing Suet Wan, et al.
Published in The Lancet Gastroenterology and Hepatology on 15 December 2022.
Summary
Background
The synergy between locoregional therapies and immune checkpoint inhibitors has not been investigated as conversion therapy for unresectable hepatocellular carcinoma. We aimed to investigate the activity of sequential transarterial chemoembolisation (TACE) and stereotactic body radiotherapy followed by avelumab (an anti-PD-L1 drug) for locally advanced, unresectable hepatocellular carcinoma.
Methods
START-FIT was a single-arm, phase 2 trial in patients with locally advanced hepatocellular carcinoma who were not suitable for curative treatment, conducted in two hospitals in Hong Kong and one in Shenzhen, China. Eligible patients were those aged 18 years or older with an Eastern Cooperative Oncology Group performance status 0–1, Child–Pugh liver function score A5 to B7, tumour size of at least 5 cm, a maximum of three tumour lesions, and adequate hepatic, renal, and bone marrow function. Participants received TACE on day 1, followed by stereotactic body radiotherapy (27·5–40·0 Gy in five fractions) at day 28. Avelumab (10 mg/kg) was administered 14 days following stereotactic body radiotherapy and every 2 weeks thereafter. The primary endpoint was the proportion of patients deemed amenable to curative treatment, defined as those who had a sustained complete or partial treatment response for at least 2 months and if curative treatment could be performed (ie, resection, radiofrequency ablation, or transplantation), analysed by intention to treat. Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03817736) and has been completed.
Findings
Between March 18, 2019, and Jan 27, 2021, 33 patients (32 [97%] men and one [3%] woman) were enrolled. The median sum of the largest diameters of lesions was 15·1 cm (IQR 8·3–14·9). 21 (64%) patients had macrovascular invasion (hepatic vein [n=13], branched portal vein [n=3], or both [n=5]). Median follow-up was 17·2 months (IQR 7·8–25·8). 18 (55%) patients were deemed amenable to curative treatment: four (12%) of 33 patients had curative treatment (resection [n=2] or radiofrequency ablation [n=2]), and 14 (42%) had a radiological complete response and opted for close surveillance. 11 (33%) of 33 patients had treatment-related adverse events that were grade 3 or worse. The most common treatment-related grade 3 or worse adverse event was transient increase in alanine aminotransferase or aspartate aminotransferase (five [15%]) after TACE. Five (15%) patients developed immune-related adverse events of grade 3 or worse (three had hepatitis, two had dermatitis).
Interpretation
To our knowledge, this is the first prospective trial using the combination of immunotherapy and locoregional treatment as conversion therapy for locally advanced unresectable hepatocellular carcinoma, with promising results. Future randomised trials with larger cohorts of patients are warranted.
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