Original Title: Eficacia de la hipertermia locorregional no invasiva coadyuvante a la radio/quimioterapia en indicaciones oncológicas - revisión sistemática y metanálisis

Authors' objectives: The main objective of this report is to evaluate the comparative efficacy of non-invasive locoregional hyperthermia (HT) used in conjunction with RT and/or CT versus treatment with RT and/or CT alone. Three specific objectives are proposed: 1. To identify the oncological indications for which there is scientific evidence regarding the efficacy of non-invasive loco-regional hyperthermia as an adjuvant treatment to RT and/or CT. 2. To evaluate the safety of non-invasive loco-regional hyperthermia as an adjuvant treatment to RT and/or CT in oncology patients. 3. To evaluate the efficacy of non-invasive loco-regional hyperthermia as an adjuvant treatment to RT and/or CT in oncology patients compared to treatment with RT and/or CT.

Authors' results and conclusions: The search strategies identified a total of 746 articles, of which 35 ultimately met the inclusion criteria and were included in the review. These 35 references corresponded to 34 independent randomized clinical trials (RCTs) that provided information on 12 different oncological indications: • Head and neck. • Rectum. • Stomach. • Liver. • Cervix. • Ovary. • Breast. • Lung. • Sarcoma. • Melanoma. • Bone (bone metastasis). • Bladder. Head and Neck The available evidence regarding the use of adjuvant hyperthermia treatment with radio/chemotherapy in head and neck cancer tumours came from a few low-quality studies with a limited number of events. HT could improve local complete response, although it does not achieve an increase in the objective response to treatment or in disease control. Regarding survival, HT did not improve overall survival rate; however, it seems to significantly enhance the intermediate variable of disease-free survival. Gastric tumours The efficacy evidence of adjuvant HT with RT and/or CT in gastric tumours was very scarce and low or very low quality and; in some locations, the evidence was limited to a single study. Adjuvant treatment with HT appears to significantly improve the complete response of the tumour and the objective response (CR + PR), although it did not significantly enhance local disease control compared to the reference treatment. Additionally, adjuvant HT treatment does not significantly improve overall survival, recurrence, or disease progression. Furthermore, the addition of HT to standard treatment did not seem to affect the patient's quality of life despite its potential adverse effects. Gynaecological tumours In gynaecological tumours, adjuvant HT combined with radiotherapy (RT) and/or chemotherapy (CT) appears to show a beneficial effect on complete tumour response, with an effect size indicating a 20 – 32 % greater likelihood of achieving a complete response with HT compared to without HT. Although this benefit was statistically significant, the subgroup analysis found no significant differences in complete tumour response between patients treated with and without HT in any of the evaluated indications: cervix, ovary and breast. HT appeared to improve complete response when administered as an adjuvant treatment with RT, while no benefit was observed when administered with CT; however, this analysis should be considered with caution due to the small number of studies involved. The addition of HT to standard treatment seemed to significantly improve the objective response to treatment (CR + PR), although little information is available on this variable. Data on local control of the disease at ≥ 3 years of follow-up are scarce and contradictory. Hyperthermia treatment appears to increase the probability of improving overall survival by 19 %, with this improvement showing a trend towards statistical significance (95 % CI of RR 1.01 – 1.41). However, when the results were analysed by tumour location and survival time, no significant differences in survival were observed between patients treated with and without HT. HT does not appear to improve disease-free survival (DFS) or local recurrence-free survival (LRFS), regardless of tumour location and follow-up time. Bone metastasis Evidence on the efficacy of adjuvant HT with RT in the treatment of bone metastases came from a single RCT, whose main methodological limitation was the lack of blinding of both patients and professionals involved in the treatment and outcome assessment, which could introduce bias in the evaluation and interpretation of the results. The study showed that adjuvant treatment with RT with HT increased the probability of complete response to pain by 30 % at 3 months, and this improvement was significant (p = 0.006), without improving the cumulative complete response rates to pain. Pain control lasted significantly longer in the RT + HT group than in the RT alone group, and the RT + HT treatment significantly improved the objective response of the lesions, with a rate of 73.4 % compared to 25 % with RT alone (p = 0.014). Quality of life improved significantly in the first month for patients who received RT + HT, although this improvement did not persist beyond the third month of treatment. Melanoma The evidence on the efficacy of adjuvant HT with RT in melanoma comes from a single RCT with a risk of bias, as it did not include blinding of either the patients or the professionals involved in the treatment and outcome assessment. This lack of blinding could affect the evaluation and interpretation of the results, which compromises the generalisation of the findings and highlight the need for more high-quality studies to confirm these results. The study showed that adjuvant treatment with RT and HT significantly improved complete response, global or objective response (CR + PR), and disease control at 2 years. There is no evidence on survival; only intermediate variables are available, so the effect of HT on the actual course of the disease remains unknown. Lung The evidence on the efficacy of adjuvant HT with RT and/or CT in NSCLC lung cancer is very limited and of very low quality, which compromises the reliability of the results. Adjuvant treatment with HT does not appear to significantly improve complete tumour response or disease control; however, it does appear to significantly improve overall or objective response to treatment (CR + PR). HT does not significantly improve overall survival rate (RR = 1.24; 95 % CI 0.66 – 2.33; p = 0.147) and no heterogeneity was observed between studies. Sarcoma The evidence on the efficacy of adjuvant HT with CT in sarcoma came from a single RCT with a risk of bias, whose main methodological limitation was the lack of blinding of both the patients and the professionals involved in the treatment and outcome assessment, which could introduce bias into the evaluation and interpretation of the results. The study showed that the addition of HT to treatment with CT significantly improved the overall or objective response (CR + PR) (CR + PR) and disease control (DC, as CR + PR + EE) to induction treatment, as well as the intermediate variables “local progression-free survival time” (p = 0.003) and “disease-free survival” (p = 0.011). However, the benefits observed in the intermediate variables did not translate into improvements in overall survival (p = 0.43). Bladder The evidence on the efficacy of adjuvant HT with RT in bladder cancer came from a single RCT and requires further high-quality studies to confirm its findings. The study showed that adjuvant RT with HT improved complete response to treatment by 22 %, and this improvement was significant, although it did not increase the disease control rate. HT did not improve overall survival at three years of follow-up. Overall assessment of the efficacy of regional hyperthermia in oncology In general, the available evidence on HT in oncology comes from low-quality randomised studies with a risk of publication bias in the main outcome variables: complete response, overall or objective response, local control of the disease and overall survival; which could affect the direction of the outcome and the true magnitude of the effect. The global meta-analysis including all available studies has shown that: • HT significantly favours complete response and objective response without significantly increasing disease control. • HT seems to significantly improve overall survival in oncology, although this analysis should be interpreted with caution, as it is derived from combining, in several cases, data from the same study (survival at different times), which could overestimate its effect. Additionally, the 95 % CI of the overall estimator was close to including the null value of non-significance, as was the case for each of the assessed indications. Furthermore, this potential benefit does not seem to occur in all indications; in rectal cancer, HT might have a negative effect on survival. • The effect of HT appears to be small, indicating the need for larger populations with a higher number of events to detect significant differences in each of the outcomes of interest. Conclusions • Evidence from randomised clinical trials has been identified for 12 oncological indications: head and neck, rectal, gastric, liver, cervix, ovary, breast, lung, sarcoma, melanoma, bone (bone metastasis) and bladder. • Overall, the evidence shows that the technology is well tolerated and safe, being almost free of additional toxicities compared to reference treatments. • The available clinical evidence on the efficacy of the technology is scarce and of low quality, indicating that it might offer benefits in certain scenarios, particularly in intermediate variables such as local response to treatment (e.g. CR); however, its benefit in variables such as overall survival is less clear. Nevertheless, there is not enough evidence to confirm these results for any of the specific indications studied. More randomised clinical trials of higher quality are needed to confirm the benefit of its use and to accurately estimate the magnitude of the effect of hyperthermia.

Authors' recommendations: A systematic review of randomized clinical trials was conducted, for which a bibliographic search was designed and carried out in the main international databases [MEDLINE (using OVID), EMBASE and the Web of Science (WOS)] up to June 2022. A critical reading of the selected articles was performed to identify methodological issues that could influence their validity, as well as an assessment of the quality of evidence following GRADE criteria. The results were presented by groups of oncological indications according to medical specialties or anatomical criteria to facilitate reading and understanding. Within each indication, the results were presented by outcome variables. Finally, a quantitative synthesis of the results was performed, estimating the calculation of the relative risk (RR) of the study variables through meta-analysis. The heterogeneity of the results was assessed, and the robustness of the findings was examined through an influence (sensitivity) analysis. The main efficacy outcomes analysed have been: • Response to treatment: Complete Response (CR), the Partial Response (PR), the Objective Response was calculated as CR + PR and the Disease Control Rate (DCR) was calculated as the percentage of patients with CR, PR, or Stable Disease (SD). • Survival: Overall Survival (OS), Free-disease Survival (FDS), Progression-free Survival (PFS). Safety outcomes were the adverse effects found in RCTs.

Project Status: Completed

URL for project: https://www.aetsa.org/publicacion/eficacia-de-la-hipertermia-locorregional-no-invasiva-coadyuvante-a-la-radio-quimioterapia-en-indicaciones-oncologicas-revision-sistematica-y-metanalisis/

Year Published: 2024

URL for published report: https://www.aetsa.org/download/AETSA-Hipertermia-coadyuvante-WEB.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Spain

DOI: 10.52766/MSDB9644

Organisation Name: Andalusian Health Technology Assessment Area

Contact Address: Area de Evaluacion de Tecnologias Sanitarias Sanitarias de Andalucia (AETSA) Avda. Innovación, s/n Edificio Arena 1. Sevilla (Spain) Tel. +34 955 006 309

Contact Name: aetsa.csalud@juntadeandalucia.es

Contact Email: aetsa.csalud@juntadeandalucia.es

Copyright: <p>Andalusian Agency for Health Technology Assessment (AETSA)</p>