EUnetHTA published an assessment of regional hyperthermia for high-risk soft tissue sarcoma treatment

In early November 2019, the report of the project OTCA18, titled “Regional hyperthermia for high-risk soft tissue sarcoma treatment” was published on the website of the European Network for HTA (EUnetHTA).

The project was executed by The Norwegian Institute of Public Health (NIPHNO) together with the Emilia-Romagna Region (RER). The dedicated reviewers come from State Health Care Accreditation Agency under the Ministry of Health of the Republic of Lithuania (VASPVT), Lithuania, Swiss Network for HTA (SNHTA) and The Carlos III Health Institute (AETS-ISCIII), Spain.

Radiation therapy can be the main treatment for sarcoma in a patient who is not healthy enough to have surgery. External beam radiation is the most commonly used treatment for soft tissue sarcoma (STS). Chemotherapy for STS generally uses a combination of several anti-cancer drugs. Doxorubicin (Adriamycin) is the most commonly used drug, alone as standard first-line chemotherapy or in combination with ifosfamide (Ifex), which can also be used as a single agent in selected cases.

The technology under assessment is regional hyperthermia added to conventional therapies to treat high-risk STS. Conventional therapies, considered as a comparator when used without hyperthermia, include adjuvant or neoadjuvant chemotherapy and/or radiotherapy.

Within Europe, the technology can be reimbursed in specific clinical situations in Germany, Switzerland, the Netherlands, Italy, Poland, and the Czech Republic. As for other EU countries, limited or no information was obtained: the technology is either not reimbursed, or decisions may be at the local level. In the USA, hyperthermia is reimbursed as a palliative treatment of various solid tumors (superficial hyperthermia) and for the treatment of advanced cervical cancer patients who cannot tolerate chemotherapy (deep hyperthermia).

Systematical search for primary studies was performed in the following databases: Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials, AMED. The search for terminated, unpublished and ongoing primary studies was performed at clinicaltrials.gov and WHO ICTRP. To rate the certainty of the evidence for each outcome, GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) was used.

Results - clinical effectiveness:

• EORTC 2010 reported 44% of deaths in the intervention group, 46% in the comparison group, and a hazard ratio (HR) for overall survival of 0.88 (95% Confidence Interval (CI) 0.64, 1.21). The median survival duration was reported to be 6.6 years (95% CI 4.5, >10) in the intervention group versus 6.1 years (95% CI 3.8, >10) in the comparison group
• EORTC 2018 reported disease-specific survival with a median duration of 15.4 years (95% CI 6.6, >17.0) in the intervention group and 6.2 years (95% CI 3.2, 10.3) in the comparison group with an HR of 0.73 (95% CI,0.54, 0.98). The survival rate in the intervention group at 10 years was 53% versus 43% in the comparison group (Risk difference (RD) 10% (95% CI -1, 21%)
• EORTC 2010 reported an objective response rate of 29% in the intervention group and 13% in the comparison group (RD 16%, 95% CI 6, 26%). EORTC 2018 reported 30% in the intervention group and 13% in the comparison group (RD 17%, 95% CI 7, 27%)
• EORTC 2018 reported an HR for disease-free survival of 0.71 (95% CI 0.55, 0.93). The median duration of disease-free survival was 2.8 years in the intervention group (95% CI 2.0, 4.9) and 1.5 years in the comparison group (95% CI 1.1, 2.1). The proportion of patients with disease-free survival at two years was 58% in the intervention group and 44% in the comparison group (RD 14%, 95% CI 3, 24%). At four years, these proportions were 42% and 35%, respectively (RD 7%, 95% CI -3, 17%)
• EORTC 2018 reported an HR for progression-free survival of 0.65 (95% CI 0.49, 0.86). The median duration of progression-free survival was 5.6 years (95% CI 2.9, 8.7) in the intervention group and 2.4 years (95% CI 1.7, 4.2) in the comparison group. The proportion of patients with progression-free survival at two years was 76% in the intervention group and 61% in the comparison group (RD 15%, 95% CI 6, 25%). At four years, these proportions were 66% and 55% (RD 11%, 95% CI 1, 21%)
• EORTC 2018 reported that within the intervention group, 9% needed an amputation versus 11% in the comparison group (RD -2%, 95% CI -11, 7%)

Results - safety:

• EORTC 2018 reported on 3.1% of patients who died due to adverse events in the hyperthermia group and 1.2% in the comparison group (RD 2%, 95% CI -1, 5%) (Issels RD et al., 2018). In Prosnitz 1999, 3.1% (95% CI 1, 9%) of patients died due to complications within a median follow-up period of 2.6 years (range 1–12.9 years). In Hayashi 2015, all patients were alive (95% CI 0, 46%) after a mean follow-up period of 10.9 years (range 8.1–17.6 years)
• EORTC 2010 reported grade 3–4 hematological toxicities, nephrotoxicities, cardiotoxicities, neurotoxicities, gastrointestinal toxicities, infections, musculoskeletal and connective tissue disorders, injuries and general disorders (Issels RD et al., 2010)

Conclusions:

• The claimed benefits of hyperthermia for high-risk STS cannot be confirmed or rejected by the currently available evidence
• Only one RCT assessed the effectiveness of this technology. It found improvements in disease-free survival, progression-free survival, and disease-specific survival, but the analysis did not adjust for competing risk, and the effect estimates may be flawed. No important effects were found for overall short-term survival, although the effect estimates were very imprecise, including both clinically meaningful benefit and harm. These estimates were based on intermediate data. No long-term data on overall survival have been published. Further research is very likely to have an important impact, which is likely to change the estimate of the effect
• Hyperthermia combined with chemotherapy and/or radiotherapy may lead to increased harm, including death from adverse events and severe leukopenia. The estimates are very uncertain

The full details in English can be found here.

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