방사선 온열치료 - 흉부종양

Abstract

평가 배경 ‘방사선 온열치료’는 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. 본 평가의 목적은 흉부종양 환자에서 방사선 온열치료의 임상적 안전성 및 효과성 등에 대한 과학적 근거를 제공하고 이를 통해 의료기술의 적정사용 등 정책적 의사결정을 지원하는 것이다.

평가 방법 흉부종양 환자에서 방사선 온열치료에 대한 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 “방사선 온열치료 소위원회(이하 ‘소위원회’라 한다)”의 심의를 거쳐 확정하였다. 소위원회 구성은 산부인과, 외과, 비뇨기과, 신경외과, 정형외과, 흉부외과 등 평가대상 암종 임상분과 각 1인과 방사선종양학과 1인, 혈액종양내과 1인, 영상의학과 1인, 근거기반의학 1인 등 총 10인으로 구성하였다. 평가의 핵심질문은 “흉부종양 환자에서 방사선 또는 항암요법과 병행하는 온열치료는 임상적으로 안전하고 효과적인가?”이었고, 안전성은 온열치료 관련 이상반응과 보고된 독성을 결과지표로 하였고, 효과성은 생존율, 관해율, 재발률, 삶의 질 등을 결과지표로 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) 2.0을 사용하여 평가하였으며, 최종 선택된 문헌을 대상으로 2명의 평가자가 독립적으로 평가를 실시하였으며, 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 Asessment, Development and Evaluation (GRADE) 방법을 이용하여 근거 수준을 평가하고, 평가 결과를 토대로 권고등급을 결정하였다.

평가 결과 방사선 온열치료와 관련한 흉부종양 문헌은 총 6편이었으며 모두 폐암을 대상으로 수행한 연구이었다. 최종 선택 문헌 6편 중 무작위 정임상연구(Randomized controlled trial, RCT)는 3편, 비무작위배정 임상연구(Non-Randomized controlled trial, NRCT) 2편, 후향적 코호트 연구(비무작위 비교연구, Non-randomized controlled study, NRS) 1편이었다. RCT 연구는 진행성 비소세포폐암 및 폐암 환자를 대상으로 수행되었으며 총 환자수는 196명, 평균 연령은 59~74.8세였다. 중재요법은 방사선요법, 화학요법, 온열치료를 모두 수행한 연구, 방사선 및 온열치료를 수행한 연구, 화학요법 및 온열치료를 수행한 연구 각각 1편씩 있었다. 온열치료의 온도는 39~44℃였고 회당 시간은 60분이었다. NRCT 1편의 연구는 모두 진행성 비소세포폐암 환자를 대상으로 수행되었으며 총 환자수는 171명, 평균 연령은 61~71세였다. 중재요법은 화학요법과 온열치료, Cyberknife, 화학요법, 온열치료의 병용요법 각 1편씩이었다. 열원은 모두 고주파였으며 온열치료 수행 온도는 40~41℃, 수행시간은 46~60분으로 주 1회 또는 2회 수행되었다. NRS는 1편이었고 대상 환자군은 비소세포폐암이었다. 26명의 환자가 포함되었으며 연령 중앙값은 중재군 62세, 비교군 69세였다. 중재요법은 방사선과 온열치료의 병용치료였으며 온열치료는 42℃에서 45~60분 간 수행되었다.

안전성 검토한 6편의 연구에서 모두 폐암 환자에서의 온열치료 안전성을 보고하였으며 연구설계에 관계없이 정리하였다. 온열치료와 직접적으로 관련있다고 보고된 이상반응은 없었다. 전체 독성을 보고한 문헌에서 급성 및 후기 독성의 발생에 있어 중재군과 비교군 간의 차이는 없었으며(p=0.58), 반점과 알레르기 반응을 보고한 피부 관련 독성 역시 군간 차이가 없었다. 3등급 이상의 호흡곤란, 급성 및 후기 폐합병증은 중재군과 비교군에서 모두 발생하지 않았다. 3등급 이상의 신장독성은 중재군에서 0~2.5%, 비교군에서 0% 발생하였고 독성 등급별 신장독성을 비교한 문헌에서 중재군과 비교군 간의 유의한 차이는 없었다(p=0.670). 한 문헌에서는 오심구토 발생에 군 간 유의한 차이가 있었고(p<0.001), 다른 문헌에서는 3등급 이상의 오심구토가 중재군에서 5.0%, 비교군에서 7.5% 발생하였으나 통계적 유의성은 보고하지 않았다. 혈액독성을 보고한 2편의 문헌 중에서 한 연구에서는 호중구 감소증, 혈소판 감소증, 빈혈 발생에 있어 중재군과 비교군 간 차이가 없었다. 다른 문헌에서는 3등급 이상의 헤모글로빈 이상은 중재군과 비교군 각각 2.5%와 2.5%, 호중구 이상은 각각 20.0%, 22.5%, 혈소판 이상은 각각 15.0%, 5.0% 발생하였고 통계적 유의성은 보고하지 않았다. 3, 4등급의 후기 척수합병증은 비교군에서만 1건(7.7%) 보고되었고 지방세포증은 군 간 유의한 차이가 없었다(p=0.5).

효과성 온열치료 효과성은 생존율, 관해율 지표에 대하여 평가하였다. RCT 문헌의 전체 생존율은 Risk ratio (RR) 1.15(95% confidence interval (CI) 0.84-1.57, I2=0.0%)로 온열치료 병용중재군과 비교군 간의 유의한 차이가 없었으나 1년 무질병 생존율은 중재군에서 67.5%, 비교군에서 12.0%로 온열치료 병용중재군에서 유의하게 높았다(p=0.036). 완전관해율, 부분관해율, 안정병변율, 진행병변율은 모두 군 간 차이가 없었으나 객관적 반응률은 온열치료 병용중재군에서 비교군 대비 유의하게 높았다(RR 1.23, 95% CI 1.03-1.48, I2=0.0%). 1편의 NRCT 문헌에서 보고한 전체 생존율은 2년 시점에서 중재군 14.6%, 비교군 13.3%로 군 간 유의성이 없었다. 2편의 NRCT 문헌 자료를 토대로 객관적 반응률에 대한 메타분석을 수행한 결과, RR 값은 1.22(95% CI 0.96-1.54, I2=0.0%)로 중재군과 비교군 간 차이가 없었다. 후향적 연구에서도 생존율을 보고하였다. 2년 전체 생존율은 온열치료 병용 중재군에서 44%, 비교군에서 15%이었으며 무국소진행 생존율은 중재군에서 76%, 비교군에서 15%로 모두 통계적으로 유의하지 않았다. 완전관해율은 중재군과 비교군에서 각각 23.1%, 7.7%이었고 부분관해율은 각각 53.8%, 46.2%이었으며 통계적 유의성은 보고하지 않았다.

결론 및 제언 체계적 문헌고찰로 폐암에서 온열치료와 방사선요법 및/또는 화학요법의 병용중재군과 방사선요법 및/또는 화학요법간의 안전성, 효과성을 평가하였다. 온열치료와 직접적으로 관련이 있는 이상반응은 보고되지 않았으며 3등급 이상의 신장독성, 폐합병증 등과 같은 심각한 이상반응 발생에 있어서 양 군의 차이가 있지 않은 점 등을 고려하여 폐암에서 온열치료를 안전한 기술로 평가하였다. 또한 온열치료 병용중재군에서의 객관적 반응률이 비교군에 비해 1.23배 높았으나, 전체생존율과 무진행생존율, 완전관해율, 부분관해율, 진행병변율은 양 군에서 유의한 차이를 보이지 않았다. 이에 소위원회에서는 본 평가결과, 폐암 환자에서 온열치료 및 방사선요법 및/또는 화학요법의 병용중재는 온도 관찰 하에 안전한 기술이며 효과성은 방사선 및/또는 화학요법과 비교하여 추가적인 치료효과가 없는 기술로 평가하였다(근거의 신뢰수준, Very Low ~ Low). 2021년 제12차 의료기술재평가위원회(2021.12.10.)에서는 소위원회 검토 결과를 논의하여 의료기술재평가사업 관리지침 제4조제10항에 의거 “흉부종양 환자에서의 방사선 온열치료”에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 방사선 온열치료는 방사선요법 및(또는) 항암화학요법과 병행하여 보조적으로 사용하는 기술로, 암종에 따라 근거가 불충분하거나 근거가 있는 경우에는 추가적인 치료효과를 확인할 수 없었다는 소위원회 결론에 동의하고, 방사선 온열치료를 암종으로 분리하지 않고 종합적으로 심의하기로 하였다. 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 온열치료, 폐암, 안전성, 효과성

Hyperthermia Combined with Radiation Therapy—Thoracic 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. This assessment aimed to provide scientific evidence for the clinical safety and effectiveness of hyperthermia combined with radiation therapy in patients with thoracic tumors and 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 thoracic tumors?" Safety was assessed based on adverse events and reported toxicity associated with hyperthermia, and effectiveness was assessed based on the survival rate, remission rate, recurrence rate, and quality of life 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 There were a total of six studies on thoracic tumors related to hyperthermia combined with radiation therapy, all of which were conducted on lung neoplasms. The six studies finally selected included three randomized controlled trials (RCTs), two non-randomized controlled trials (NRCTs), and one retrospective cohort study (non-randomized controlled study; NRS). RCTs were conducted in patients with advanced non-small cell lung cancer (NSCLC) and lung neoplasms. The total number of patients was 196. Their age ranged from 59 to 74.8 years. One study used hyperthermia with radiation therapy and chemotherapy, another used hyperthermia with radiation therapy, and yet another used hyperthermia with chemotherapy. The temperature for hyperthermia was 39–44℃, and the time per session was 60 min. One NRCT was conducted in patients with NSCLC (n = 171), with an age range of 61 to 71 years. One NRCT used hyperthermia with chemotherapy, and the other used hyperthermia with CyberKnife and chemotherapy. All of the heat sources were high-frequency waves, and hyperthermia was conducted at a temperature of 40–41℃ for 46–60 min, once or twice a week. The NRS was conducted in patients with NSCLC. Twenty-six patients were included, with a median age of 62 years in the intervention group and 69 years in the control group. The intervention involved hyperthermia combined with radiation therapy, where hyperthermia was conducted at a temperature of 42℃ for 45–60 min.

Safety All six studies reviewed reported the safety of hyperthermia in patients with lung neoplasms. No adverse events directly related to hyperthermia were reported. In the studies reporting overall toxicity, the incidence of acute and late toxicities did not differ between the intervention and control groups (p = 0.58). Similarly, skin-related toxicities reporting spots and allergic reactions did not differ between the groups. Severe dyspnea of grade 3 or more and acute and late pulmonary complications did not occur in either the intervention or control group. Nephrotoxicity of grade 3 or more occurred in 0–2.5% of the intervention group and 0% of the control group, although there was no significant difference between the intervention and control groups in the studies comparing nephrotoxicity by grade (p = 0.670). One study reported a significant difference in the incidence of nausea and vomiting (p < 0.001) between the groups, and another study reported severe nausea and vomiting of grade 3 or more in 5.0% of the intervention group and 7.5% of the control group, with no statistical significance between the groups. In one of two studies reporting hematologic toxicities, the incidence of neutropenia, thrombocytopenia, and anemia did not differ significantly between the intervention and control groups. The other study reported severe hemoglobin abnormalities of grade 3 or more in 2.5% in each of the intervention and control groups; neutrophil abnormalities in 20.0% and 22.5%, respectively; and platelet abnormalities in 15.0% and 5.0%, respectively, but with no statistical significance in the differences. One case (7.7%) of grade 3 or 4 late myelopathy was reported only in the control group, and there was no significant difference in adipocytes between the groups (p = 0.5).

Effectiveness The effectiveness of hyperthermia was assessed based on the survival rate and remission rate indices. In terms of the overall survival (OS) in the RCT, there was no significant difference between the intervention (using hyperthermia combination therapy) and control groups, with a risk ratio (RR) of 1.15 (95% confidence interval [CI] 0.84–1.57, I2 = 0.0%). The 1-year disease-free survival (DFS) was 67.5% in the intervention group and 12.0% in the control group, which was significantly higher in the intervention group (p = 0.036). There was no significant difference between the groups in terms of complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD), although the objective response rate was significantly higher in the intervention group using combination therapy with hyperthermia than in the control group (RR 1.23, 95% CI 1.03–1.48, I2 = 0.0%). The OS rate reported in one NRCT study was 14.6% in the intervention group and 13.3% in the control group at 2 years, with no significant difference between the groups. As a result of performing a meta-analysis on the objective response rate based on the data of two NRCT studies, the RR value was 1.22 (95% CI 0.96–1.54, I2 = 0.0%), indicating no difference between the intervention and control groups. Survival rates were also reported in a retrospective study. The 2-year OS rate was 44% in the intervention group using hyperthermia combination therapy and 15% in the comparison group, while the local progression-free survival was 76% in the intervention group and 15% in the comparison group, which was not statistically significantly different. The CR was 23.1% and 7.7% in the intervention and control groups, respectively, and the PR was 53.8% and 46.2% in the intervention and control groups, respectively, with no statistically significant difference.

Conclusions and Recommendations This systematic literature review evaluated the safety and effectiveness of hyperthermia combined with radiation therapy and/or chemotherapy in patients with lung neoplasms. No adverse events directly associated with hyperthermia were reported. Considering that there were no significant differences between the groups in terms of severe adverse events, such as grade 3 or more nephrotoxicity or pulmonary complications, hyperthermia was assessed to be a safe treatment for lung neoplasms. In addition, the objective response rate in the intervention group using hyperthermia combination therapy was 1.23 times higher than that of the control group, although there were no significant differences in OS, PFS, CR, PR, and PR between the two groups. Based on this assessment, the Subcommittee evaluated hyperthermia, with a controlled temperature, combined with radiation therapy and/or chemotherapy in patients with lung neoplasms as a safe technique. However, it was assessed as having no additional therapeutic effect compared with radiation and/or chemotherapy alone (confidence level of evidence: very low to low). The 12th Health Technology Reassessment Committee in 2021 (December 10, 2021) reviewed hyperthermia combined with radiation therapy in patients with thoracic tumors 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 agreed with the decision of the Subcommittee that hyperthermia was a technique that could be used as an adjuvant treatment with radiation therapy and/or chemotherapy, but stated that there was insufficient evidence and that additional therapeutic effects were not confirmed, even when some evidence was presented, depending on the cancer type. It was decided to review radiation hyperthermia comprehensively without analyzing it by separate cancer types. 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, Induced hyperthermia, Lung neoplasms, Safety