방사선 온열치료 - 두경부 종양

Abstract

평가 배경 ‘방사선 온열치료 및 온열치료계획’은 신체 조직을 고온(최대 45 ℃)에 노출시켜 정상 조직에 대한 손상을 최소화하면서 암세포를 치사시키는 암 치료법으로 방사선 요법 또는 항암요법과 함께 사용하며 암세포를 손상, 치사시키거나 방사선 또는 항암제에 더 예민하게 반응하도록 하는 기술이다. 2005년 1월부터 행위비급여 항목으로 사용되고 있으며, 건강보험심사평가원 예비급여부에서 해당 기술의 급여적용 타당성 판단 등 의사결정에 필요한 근거자료를 도출하기 위해 해당 행위의 재평가를 의뢰하였다(2021.03.23.). 본 평가의 목적은 두경부 종양 환자에서 방사선 온열치료의 임상적 안전성 및 효과성 등에 대한 과학적 근거를 제공하고 이를 통해 의료기술의 적정사용 등 정책적 의사결정을 지원하는 것이다.

평가 방법 두경부 종양 환자에서 방사선 온열치료에 대한 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 “방사선 온열치료 재평가 소위원회(이하 ‘소위원회’라 한다)”의 심의를 거쳐 확정하였다. 소위원회 구성은 임상분과(산부인과, 외과, 비뇨기과, 신경외과, 정형외과, 흉부외과) 각 1인, 방사선종양학과 1인, 혈액종양내과 1인, 영상의학과 1인, 근거기반의학 1인의 총 10인으로 구성하였다. 평가의 핵심질문은 “두경부 종양 환자에서 방사선 또는 항암요법과 병행하는 방사선 온열치료는 임상적으로 안전하고 효과적인가?”이었다. 안전성은 장기별로 보고된 독성을 지표로, 효과성은 생존율, 관해율, 재발률, 국소조절률 등을 주요 지표로 평가하였다. 체계적 문헌고찰은 핵심질문을 토대로 국외 3개, 국내 5개 데이터베이스에서 검색하였으며, 문헌 선정과정은 문헌선택 및 배제기준에 따라 2명의 평가자가 독립적으로 수행하고, 의견의 불일치가 있는 경우에는 평가자 간 합의를 통해 최종 논문을 결정하였다. 문헌의 비뚤림위험 평가는 Cochrane의 Risk of Bias (RoB) 및 Risk of Bias Assessment tool for Non-randomised Study (RoBANS)를 사용하여 평가하였다. 최종 선택된 문헌을 대상으로 2명의 평가자가 독립적으로 평가를 시행하였으며, 의견이 불일치한 경우 평가자 간 합의를 통해 일치된 결과를 도출하였다. 모든 자료는 연구단위로 추출하였다. 본 평가에서 수행한 체계적 문헌고찰 결과는 암종 단위로 결과제시 및 Grading of Recommendations Assessment, Development and Evaluation (GRADE) 방법을 이용하여 근거 수준을 평가하고, 평가 결과를 토대로 권고등급을 결정하였다.

평가 결과 본 평가에 최종 선택된 문헌은 총 6편으로, 세부 암종별로 구인두암을 대상으로 한 문헌은 총 5편(RCT 4편, NRCT 1편)이 포함되었고, 안암을 대상으로 한 문헌은 NRCT 1편이 포함되었다. 구인두암 환자를 대상으로 한 연구의 총 대상자는 532명이었고, 안암 환자를 대상으로 한 연구의 총 대상자는 113명이었다. 중재군에서는 방사선 온열치료와 화학요법, 방사선요법을 병용한 군이었고(이하 ‘중재군’), 대조군은 화학요법과 방사선요법을 사용한 군(이하 ‘대조군’)이었다.

구인두암 구인두암 환자에서 방사선 온열치료를 병용중재한 연구는 총 5편으로 RCT 4편과 NRCT 1편이 선택되었다. 연구수행국가는 모두 아시아에서 수행된 연구였으며, 총 환자수는 532명이 포함되었다. 중재치료는 방사선요법과 온열치료 혹은 방사선요법, 화학요법과 온열치료의 병용치료였다. RCT 4편의 비뚤림위험 평가 결과는 1편의 문헌에서 본문과 표의 결과가 상이해 ‘높음’으로 평가하였고, 배정순서 은폐에 대한 언급이 4편 모두 없어 ‘불확실’로 평가하였다. 그 외 비뚤림위험은 낮았다.

구인두암 안전성 구인두암 환자를 대상으로 한 4편의 문헌 중 방사선 온열치료와 직접적으로 연관 있는 부작용을 보고한 1편에서 방사선 온열치료로 인해 중재군에서 1-2등급의 피부화상이 발생했다고 보고하였다(2.3%).

구인두암 효과성 구인두암 환자를 대상으로 한 방사선 온열치료와 관련된 효과성은 생존율, 관해율, 재발률, 기타(원격 전이율, 국소조절률) 지표를 기준으로 평가하였다. 구인두암 환자에서 전체 생존율(RCT 3편)은 메타분석 결과 중재군에서 통계적으로 유의하게 높게 나타났다(RR 1.23, 95% CI 1.03, 1.47, I2=26%). 무질병 생존율(2편; HR 0.57, 95% CI 0.34, 0.96; 51.3% vs 21%, p=0.001), 무진행 생존율(1편; 69.1% vs 58.7%, p=0.039)은 모두 중재군에서 유의하게 높았다. 국소 무진행 생존율(RCT 2편)은 메타분석 결과 중재군에서 통계적으로 유의하게 높았다(2편, RR 1.20, 95% CI 1.10, 1.31, I2=0%). 관해율 관련 지표 중 완전 관해율(RCT 4편)은 방사선 요법과 비교한 메타분석 결과 중재군에서 통계적으로 유의하게 높았고(RR 1.67, 95% CI 1.12, 2.48, I2=60%), NRCT 1편의 완전 관해율은 중재군 33.3%, 대조군 41.6%이었으나 두 군간 차이에 대한 통계적 유의수준은 보고하지 않았다. 부분 관해율(RCT 3편)은 메타분석 결과 대조군에서 더 높게 나타났으나 이질성이 높았다(RR 0.59, 95% CI 0.23, 1.49, I2=84%). NRCT 1편에서 부분 관해율은 중재군 50.0%, 대조군 41.6%이었으나 두 군간 차이에 대한 통계적 유의수준은 보고하지 않았다. 객관적 관해율(RCT 3편)은 메타분석 결과 두 군간 차이가 통계적으로 유의하지 않았으며, 연구들간 이질성이 매우 높았다(RR 1.14, 95% CI 0.81, 1.59, I2=92%). NRCT 1편에서는 중재군과 대조군 모두 객관적 관해율이 83.3%로 차이가 없었다. 불완전 관해율 및 안정 병변율(RCT 2편)은 메타분석 결과 대조군에서 유의하게 더 높았다(RR 0.55, 95% CI 0.34, 0.88, I2=0%). 무 관해율을 보고한 RCT 1편의 결과는 중재군 0.0%, 대조군 3.8%로, 두 군간 통계적으로 유의한 차이가 없다고 보고하였고(p>0.05), NRCT 1편에서의 결과는 중재군과 대조군 모두 16.6%로 차이가 없었다. 진행 병변율(RCT 2편)은 메타분석 결과 두 군간 통계적으로 유의한 차이가 없었다(RR 0.87, 95% CI 0.21, 3.56, I2=50%). 재발률율은 RCT 1편에서 보고하였고, 연구대상자 154명 중 8명에서 구인두암이 재발하였다고 보고하였으나 중재군과 대조군 중 어느 군에서의 재발인지 구체적으로 밝히지 않았다. 기타 관련 지표인 원격 전이율은 RCT 1편에서 중재군 36.8%, 대조군 44%이었으나 두 군간 차이에 대한 통계적 유의수준을 보고하지 않았고, 국소 조절룰(RCT 2편)은 메타분석 결과 중재군에서 더 효과가 높았다(RR 1.20, 95% CI 1.10, 1.31, I2=0%).

안암 안암 환자에서 온열치료를 병용중재 한 연구는 NRCT 1편이 선택되었다. 연구수행국가는 미국이었으며, 망막아세포종 환자 113명을 대상으로 하였다. 환자 연령은 평균 9개월의 신생아였으며, 중재치료는 화학요법과 온열치료를 병용사용하였다. 비뚤림위험을 평가한 결과, 무작위 배정순서은폐에 대한 언급이 없어 ‘불확실’로 평가하였으며, 선택적 보고에 대해서는 ‘높음’으로 평가하였다.

안암 안전성 안암 환자에서 방사선 온열치료와 관련한 안전성 결과는 보고되지 않았다.

안암 효과성 안암 환자의 방사선 온열치료와 관련된 효과성은 재발률로 평가하였다. 안암 환자에서는 NRCT 1편에서 재발률을 중재군 54.2%, 대조군 25.8%로 보고하였으나, 두 군간 유의수준을 보고하지 않았다.

결론 및 제언

구인두암 구인두암에서 방사선 온열치료와 방사선 화학요법 또는 방사선요법의 병용중재군과 방사선 화학요법 또는 방사선 치료군을 비교한 RCT 문헌 4편과 NRCT 문헌 1편을 최종 선택하였다. 구인두암 환자에서 방사선 온열치료와 관련된 안전성 결과로 피부화상(3.3%)이 보고되었으며, 그 외 화학치료와 관련된 안전성 결과로 혈액학적, 구강계, 피부관련, 위장관계 독성이 발생하였으나 모든 지표에서 두 군간 차이가 없었다. 효과성은 중재군이 비교군에 비해 전체생존율, 무질병 생존율, 무진행 생존율, 국소 무진행 생존율, 완전 관해율, 국소 조절률은 통계적으로 유의하게 개선되었으나, 그 외 부분 관해율, 객관적 관해율 등 기타 지표에서는 두 군간 유의한 차이를 확인할 수 없었다. 이에 소위원회에서는 구인두암 환자에서 방사선 온열치료는 방사선 화학요법 또는 방사선요법과 같이 사용하는 경우 온도 관찰 하에 시술될 경우 안전한 기술이나 추가적인 치료효과가 없는 기술로 평가하였다(근거의 신뢰수준, Very Low ~ Moderate).

안암 안암 환자를 대상으로 방사선 온열치료와 화학요법의 병용중재에 대한 체계적 문헌고찰 결과, 선택문헌은 NRCT 문헌 1편이었다. 안전성 결과는 보고하지 않아 평가할 수 없었고, 효과성 지표로 재발률을 보고하였으나, 두 군간 유의수준을 보고하지 않았다. 이에 소위원회에서는 안암 환자에서 방사선 온열치료와 화학요법의 병용중재에 대한 안전성과 효과성을 판단하기에 근거가 부족한 것으로 평가하였다(근거의 신뢰수준, Very Low). 2021년 제12차 의료기술재평가위원회(2021.12.10.)에서는 소위원회 검토 결과에 근거하여 의료기술재평가사업 관리지침 제4조제10항에 의거 “구인두암 환자에서 방사선 온열치료”와 “안암 환자에서 방사선 온열치료”에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 방사선 온열치료가 2004년 비급여 항목으로 고시되어 10년 이상 사용되어 왔음에도 근거가 충분하지 않음을 고려하여 암환자에서의 방사선 온열치료를 “권고하지 않음”으로 심의하였다(권고등급: 권고하지 않음).

주요어 두경부암, 방사선 온열치료, 안전성, 효과성

Hyperthermia Combined with Radiation Therapy—Head and Neck Tumors

Background Hyperthermia combined with radiation therapy is a cancer treatment intended to kill cancer cells while minimizing damage to normal tissues. It involves exposing body tissues to high temperatures (up to 45℃), which damage or kill cancer cells or make them more susceptible to radiation or chemotherapy. As it has been considered an out-of-pocket treatment since January 2005, the Preliminary Benefit Department of the Health Insurance Review and Assessment Service requested a reassessment of the act to obtain the necessary data for decision-making, such as determining the feasibility of applying the technique (March 23, 2021). This assessment aimed to provide scientific evidence for the clinical safety and effectiveness of hyperthermia combined with radiation therapy in patients with head and neck tumors to support policy decisions related to the appropriate use of health technology.

Methods A systematic literature review was conducted to evaluate the safety and effectiveness of hyperthermia with radiation in patients with gastrointestinal tumors. All assessment methods were finalized after deliberation by the Subcommittee on Hyperthermia Combined with Radiation Therapy (hereinafter referred to as the "Subcommittee"), considering the purpose of the assessment. The subcommittee consisted of 10 members: one each from clinical departments of obstetrics and gynecology, surgery, urology, neurosurgery, orthopedic surgery, and thoracic surgery; one from radiation oncology; one from hematology and oncology; one from radiology; and one from evidence-based medicine. The key question in the assessment was: "Is hyperthermia combined with radiation therapy or chemotherapy clinically safe and effective in patients with head and neck tumors?" Safety was assessed based on the toxicity reported in each organ, and effectiveness was assessed based on the survival, remission, recurrence, and local control rates as indicators. Based on the key question, three overseas and five domestic databases were used for the systematic literature review. Studies were selected independently by two assessors according to the literature inclusion and exclusion criteria. In the event of any disagreement, consensus was reached by discussion among the assessors. The risk-of-bias (ROB) in the included studies was assessed two assessors independently using Cochrane's Risk-of-Bias tool and the Risk-of-Bias Assessment tool for Non-randomized Studies 2.0. In the event of any disagreement, decisions were made by achieving consensus through discussion among the assessors. All data were extracted by study unit. For the results of the systematic literature review, the level of evidence was assessed by presenting the results by using the Grading of Recommendations, Assessment, Development, and Evaluation. The recommendation grade was determined based on the assessment results.

Results Six articles were finally selected for this assessment, with five studies (four randomized controlled trials [RCTs] and one non-RCT [NRCT]) on oropharyngeal cancer and one NRCT on eye cancer. The total number of subjects was 532 in the studies on oropharyngeal cancer selected and 113 in the study on eye cancer. The intervention group was subjected to a combination of hyperthermia, chemotherapy, and radiation therapy, and the control group was subjected to chemotherapy and radiation therapy.

Oropharyngeal cancer Five studies (four RCTs and one NRCT) on oropharyngeal cancer applied hyperthermia with radiation therapy. All studies were conducted in Asia and included a total of 532 patients. The intervention was hyperthermia combined with radiation therapy and/or chemotherapy. ROB assessment of the four RCTs revealed that the ROB was high in one study due to differences in the results presented in a table and in the main text and uncertain for all studies with no mention of allocation concealment. The ROB was assessed as low for all other indicators.

Safety in oropharyngeal cancer patients Among the four studies on oropharyngeal cancer patients, one reported adverse events directly related to hyperthermia combined with radiation therapy, in the form of grade 1–2 skin burns caused by hyperthermia combined with radiation therapy in 2.3% of the subjects in the intervention group.

Effectiveness against oropharyngeal cancer Effectiveness of hyperthermia combination therapy in patients with oropharyngeal cancer was assessed based on the toxicity reported in each organ, and effectiveness was assessed based on the survival rate, remission rate, recurrence rate, and other indicators (distant metastasis and local control rates). In a meta-analysis, the overall survival (OS) (three RCTs) in patients with oropharyngeal cancer was significantly higher in the intervention group (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.03–1.47, I2 = 26%). Both disease-free survival (DFS) (two studies; hazard ratio 0.57, 95% CI 0.34–0.96; 51.3% vs 21%, p = 0.001) and progression-free survival (PFS, one study; 69.1% vs 58.7%, p = 0.039) were significantly higher in the intervention group. In the meta-analysis, the local progression-free survival (LPFS) (two RCTs) in patients with oropharyngeal cancer was significantly higher in the intervention group (two studies, RR 1.20, 95% CI 1.10–1.31, I2 = 0%). Among the remission rate-related indicators, a meta-analysis showed that the complete remission rate (four RCTs) was statistically significantly higher in the intervention group than in the group receiving radiation therapy alone (RR 1.67, 95% CI 1.12–2.48, I2 = 60%). While the remission rate was 33.3% in the intervention group and 41.6% in the control group in one NRCT, no statistically significant difference was reported between the groups. The partial remission rate (three RCTs) was statistically significantly higher in the control group, but with a high level of heterogeneity (RR 0.59, 95% CI 0.23–1.49, I2 = 84%). The partial remission rate in one NRCT was 50.0% in the intervention group and 41.6% in the control group, although the difference between the groups was not statistically significant. The meta-analysis revealed no statistically significant difference in the objective remission rate (three RCTs) between the two groups, albeit with a high level of heterogeneity (RR 1.14, 95% CI 0.81–1.59, I2 = 92%). In one NRCT, the objective remission rate was 83.3% in both the intervention and control groups, indicating no difference. The incomplete remission rate and stable disease rate (two RCTs) were statistically significantly higher in the control group (RR 0.55, 95% CI 0.34–0.88, I2 = 0%). One RCT that reported the non-remission rate found no significant difference, at 0.0% in the intervention group and 3.8% in the control group (p > 0.05), and one NRCT also reported no difference at 16.6% for both the intervention and control groups. The meta-analysis found no statistically significant difference in the progressive disease rate (two RCTs) between the two groups (RR 0.87, 95% CI 0.21–3.56, I2 = 50%). In one RCT reporting the recurrence rate, oropharyngeal cancer was reported to have recurred in eight of 154 subjects, although it was not mentioned to which group these eight patients belonged. The distant metastasis rate in one RCT was 36.8% in the intervention group and 44% in the control group, with no statistically significant difference between the groups. The meta-analysis revealed that the local control level (two RCTs) was higher in the intervention group (RR 1.20, 95% CI 1.10–1.31, I2 = 0%).

Eye cancer One NRCT describing application of hyperthermia with radiation therapy in eye cancer patients was selected. The study was conducted in the United States, in 113 patients with retinoblastoma. The patients were 9 months of age on average, and the intervention involved hyperthermia combined with chemotherapy. There was no mention of allocation concealment, resulting in an ROB assessment of “uncertain,” while the ROB was assessed as “high” for selective reporting.

Safety in eye cancer patients None of the included papers reported results on the safety of using hyperthermia combined with radiation therapy in patients with eye cancer.

Effectiveness against eye cancer The effectiveness of hyperthermia combined with radiation therapy in patients with eye cancer was assessed based on the recurrence rate. In one NRCT, the recurrence rate was reported to be 54.2% in the intervention group and 25.8% in the control group, without reporting whether the differences between the groups reached statistical significance.

Conclusions and Recommendations

Oropharyngeal cancer Four RCTs and one NRCT on oropharyngeal cancer, comparing the intervention group using hyperthermia with radiation therapy and/or chemotherapy with the control group only using radiation therapy and/or chemotherapy, were finally selected. Regarding safety in patients with oropharyngeal cancer, skin burns (3.3%) were reported as an outcome related to hyperthermia combined with radiation therapy, and hematological, oral, skin, and gastrointestinal toxicities related to chemotherapy were reported, indicating no difference between the two groups in any of the indicators. In terms of effectiveness, the intervention group showed statistically significant improvements in the OS, DFS, PFS, LPFS, complete remission rate, and local control rate as compared with the control group. In terms of other indicators, such as partial remission rate and objective remission rate, no significant difference was found between the two groups. The Subcommittee determined that hyperthermia, with controlled temperature, combined with radiation therapy and/or chemotherapy in patients with oropharyngeal cancer was a safe technique. However, it was assessed as having no additional therapeutic effect (confidence level of evidence: very low to moderate).

Eye cancer This systematic literature review on the use of hyperthermia combined with radiation therapy and/or chemotherapy in patients with eye cancer identified one eligible NRCT. Safety could not be assessed, as such results were not reported. While the recurrence rate was reported as an indicator of effectiveness, although the level of significance of differences between the two groups was not reported. The Subcommittee determined that there was not sufficient evidence for judging the safety and effectiveness of hyperthermia combined with radiation therapy and/or chemotherapy in patients with eye cancer (confidence level of evidence: very low). The 12th Health Technology Reassessment Committee in 2021 (December 10, 2021) reviewed hyperthermia combined with radiation therapy in patients with oropharyngeal cancer and hyperthermia combined with radiation therapy in patients with eye cancer as follows in accordance with Article 4, Paragraph 10 of the Health Technology Reassessment Project Management Guidelines based on the results of the Subcommittee review: The Health Technology Reassessment Committee determined that hyperthermia combined with radiation therapy in cancer patients was not recommended due to a lack of evidence, even though it had been used for more than 10 years since being designated as an out-of-pocket item in 2004 (recommendation level: not recommended).

Keywords: Effectiveness, Safety, Head and neck cancer, Hyperthermia