방사선 온열치료 - 부인 종양

Abstract

평가 배경 ‘방사선 온열치료’는 신체 조직을 고온(최대 45℃)에 노출시켜 정상 조직에 대한 손상을 최소화하면서 암세포를 치사시키는 암 치료법으로 방사선요법 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 부인 종양 환자에서 방사선 온열치료의 임상적 안전성 및 효과성 등에 대한 과학적 근거를 제공하고 이를 통해 의료기술의 적정 사용 등 정책적 의사결정을 지원하는 것이다.

평가 방법 부인 종양 환자에서 방사선 온열치료에 대한 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가 방법은 평가 목적을 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 “부인 종양 환자에서 방사선 또는 항암요법과 병행하는 방사선 온열치료는 임상적으로 안전하고 효과적인가?”이었고, 안전성은 방사선 온열치료 관련 이상반응과 보고된 독성을 결과지표로 하였고, 효과성은 전체 생존율, 무질병 생존율, 관해율, 국소 조절률, 국소 재발률 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 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 Assessment, Development and Evaluation (GRADE) 방법을 이용하여 근거 수준을 평가하고, 평가 결과를 토대로 권고등급을 결정하였다.

평가 결과

자궁경부암 본 평가에서 부인 종양은 암종별로 자궁경부암, 난소암 문헌이 있었고, 최종 선택문헌은 12편(9개 연구)이었다. 이 중 자궁경부암 문헌 10편(7개 연구)이었고, 무작위배정 임상연구(Randomized controlled trial, RCT)는 총 9편(6개 연구)이었고, 전향적 코호트 연구가 1편이었다. 자궁경부암 RCT 연구의 총 환자수는 1,010명이었고, 평균 나이의 범위는 45~64.9세였다. 방사선 온열치료의 온도는 39.5~43℃였고, 회당 시간은 55~90분, 주 1~3회를 시행하였다. 비뚤림위험 평가 결과에서는 선택적 결과보고, 불충분한 결과자료, 민간연구비 지원 등에서 비뚤림위험이 ‘높음’으로 평가된 연구가 있었다. 자궁경부암 대상 전향적 코호트 연구(Lee 등, 2017) 1편의 연구 국가는 한국이었고, 대상자는 재발성 자궁경부암 환자로 1차 치료에서 완전관해 후 재발한 환자를 모집하였다. 환자수는 38명, 평균 연령은 50.8세였다. 중재는 방사선 온열치료와 화학요법을 병행하고, 온도는 39.8~41.9℃, 60분/회, 주 3회를 시행하였다. 비뚤림위험 평가 결과, 교란변수 항목만 ‘불확실’이었고, 그 외 영역은 비뚤림위험은 ‘낮음’으로 평가하였다.

자궁경부암 안전성 방사선 온열치료 관련 부작용을 보고한 연구는 총 2개(RCT 1개, 전향적 코호트 1개) 연구에서 보고하였고, RCT 연구에서는 1~2℃의 지방층 화상이 방사선 온열치료군(9.5%)에서 비교군(1%)보다 통계적으로 유의하게 더 많이 발생하는 것으로 보고하였으나(P-value 0.02) 추적관찰 결과에서는 두 군간 차이가 없다고 보고하였다. 전향적 코호트 연구는 방사선 온열치료군에서만의 부작용 발생을 보고하였고, 비교군의 결과는 보고하지 않았다. 방사선 온열치료 관련 후기 독성은 0명이었고, 복부 불편감 및 열감은 44.4%에서 발생했다고 보고하였다. 그 외 비뇨기계, 위장관계, 신장, 혈액, 피부 등 장기별로 독성을 보고하였으나, 두 군간 차이를 보이는 심각한 부작용은 없었고, 이러한 장기별 독성은 방사선 온열치료 관련 부작용이라기보다 방사선 또는 화학요법으로 인한 부작용으로 소위원회에서는 판단하였다.

자궁경부암 효과성 방사선 온열치료 효과성은 전체 생존율, 무질병 생존율, 관해율, 국소 조절률, 국소 재발률 등을 결과지표로 평가하였다. RCT 연구에서 방사선 온열치료 및 방사선화학요법 또는 방사선요법 병용요법군은 방사선화학요법 또는 방사선요법군과 비교해 완전관해율은 1.23배 더 개선시키는 것으로 나타났다(Risk ratio (RR) 1.23, 95% Confidence interval (CI) 1.02~1.50, I2=0.0%). 하지만, 그 외 결과지표인 전체 생존율(RR 1.03, 95% CI 0.92~1.16, I2=0.0%), 무질병 생존율(RR 1.14, 95% CI 0.82~1.59, I2=0.0%), 무국소진행 생존율(RR 1.10, 95% CI 0.96~1.25, I2=30.7%), 부분관해율(RR 0.73, 95% CI 0.51~1.05, I2=0.0%), 안정병변율(RR 0.26, 95% CI 0.06~1.19, I2=0.0%), 객관적 관해율(RR 1.03, 95% CI 0.83~1.26, I2=0.0%), 원격전이율(RR 0.87, 95% CI 0.37~1.60, I2=18.8%) 등은 메타분석 결과 두 군간 통계적으로 유의한 차이가 없었다. 또한, 1편밖에 보고하지 않아 메타분석이 불가능한 결과지표인 국소 조절률, 골반 종양 조절률, 진행병변율, 국소 재발률, 골반 종양 재발률 등도 두 군간 차이를 보고한 결과지표는 없었다. 전향적 코호트 1편에서는 무질병 생존율은 두 군간 차이가 없다고만 보고하였고(P-value 0.235), 관해율은 치료 완료 후 시점과 추적관찰 시점 결과를 보고하였고, 방사선 온열치료 및 화학치료 병용요법군이 화학치료군에 비해 통계적으로 유의하게 관해율이 높은 것으로 보고하였다.

난소암 난소암 선택문헌은 2편이었고, RCT 1편, 비무작위배정연구 임상연구(Non-randomized controlled trial, NRCT) 1편이었다. 난소암 RCT 연구는 심한 복수가 동반된 진행성 난소암 환자 48명을 대상으로 하였고, 중재는 방사선 온열치료와 화학요법을 병용하였고, 온도는 42.5~43℃였고, 회당 시간은 60분, 주 2회, 총 8회를 시행하였다. 비뚤림위험 평가 결과에서는 선택적 결과보고, 불충분한 결과자료 영역에서 비뚤림위험이 ‘높음’으로 평가되었다. NRCT 연구는 진행성 난소암 환자 73명 대상으로 하였고, 중재는 방사선 온열치료와 화학요법을 병행하였고, 온도는 42.5~43.5 ℃, 회당 시간은 60~120분, 주 2~3회, 총 8회를 시행하였다. 비뚤림위험 평가에서는 배정순서 은폐만 ‘불확실’이었고, 그 외 영역은 비뚤림위험은 ‘낮음’으로 평가하였다.

난소암 안전성 난소암 선택문헌 중 방사선 온열치료 관련 부작용을 보고한 연구는 없었고, 전반적인 독성, 혈액학적 독성, 위장관계 독성 등을 보고하였고, 두 군간 차이를 보이는 심각한 부작용은 없었고, 이러한 장기별 독성은 방사선 온열치료 관련 부작용이라기보다 방사선 또는 화학요법으로 인한 부작용으로 소위원회에서는 판단하였다.

난소암 효과성 RCT 연구에서는 방사선 온열치료 및 화학요법 병용중재군이 화학요법군에 비해 국소 조절률(중재군 75%, 비교군 54.2%)과 치료반응(완전관해율 중재군 16.7%, 비교군 4.2%; 부분관해율 중재군 33.3%, 비교군 20.8%; 안정병변율 중재군 25%, 비교군 29.2%; 진행병변율 중재군 25%, 비교군 45.8%)은 통계적으로 유의하게 개선효과가 있다고 보고하였고(P-value <0.05), 전체 생존율은 두 군간 통계적으로 유의한 차이가 없었다(P-value 0.672). NRCT 연구에서는 방사선 온열치료 및 화학요법 병용중재군이 화학요법군에 비해 종양관해율(중재군 83.3%, 비교군 43.2%)은 통계적으로 유의하게 개선효과가 었었고(P-value <0.05), 전체 생존율은 중재군 41.6%, 비교군 62.1%였으나 두 군간 차이에 대한 검증결과는 보고하지 않았다.

결론 및 제언

자궁경부암 체계적 문헌고찰로 자궁경부암에서 방사선 온열치료 및 방사선화학요법 또는 방사선치료 병용중재군과 방사선화학요법 또는 방사선치료군을 비교한 결과, 화상(1~2℃), 열감 등이 방사선 온열치료군에서 더 많이 발생하여 주의가 필요하나 심각한 부작용의 발생이 증가하지 않는 점 등을 고려해 안전한 기술로 평가하였다. 또한, 효과성은 완전관해율이 방사선 온열치료 및 방사선화학요법 또는 방사선치료 병용중재군이 방사선화학요법 또는 방사선치료군에 비해 1.23배 통계적으로 유의하게 개선되었으나, 그 외 결과지표인 전체 생존율, 무질병 생존율, 무국소진행 생존율, 국소 조절률, 골반 조절률, 부분관해율, 안정병변율, 진행병변율, 객관적 관해율, 국소 재발률, 골반 종양 재발률, 원격 전이율에서는 두 군간 차이가 없었다. 이에 소위원회에서는 본 평가 결과, 자궁경부암 환자에서 방사선 온열치료 및 방사선화학요법 또는 방사선치료 병용중재는 온도 관찰 하에 안전한 기술이며, 효과성은 방사선화학요법 또는 방사선치료와 비교해 추가적인 치료효과가 없는 기술로 평가하였다(근거의 신뢰수준, Moderate).

난소암 난소암에서 방사선 온열치료 및 화학요법 병용중재에 대한 체계적 문헌고찰 결과, 방사선 온열치료 관련 부작용은 보고하지 않았고, 화학요법 관련 독성(혈액학적 부작용)은 두 군간 차이가 없었다고 보고하였다. 효과성 지표에서 치료반응과 국소 조절률은 방사선 온열치료 및 화학요법 병용중재군이 화학요법군에 비해 통계적으로 유의하게 개선되었다고 보고하였으나, 전체 생존율은 두 군간 차이가 없었다. 이에 소위원회에서는 본 평가 결과, 난소암 환자에서 방사선 온열치료 및 화학요법 병용중재는 선택문헌이 RCT 1편과 NRCT 1편으로 방사선 온열치료의 안전성과 효과성을 판단하기에 근거가 불충분한 것으로 평가하였다(근거의 신뢰수준, Moderate). 2021년 제12차 의료기술재평가위원회(2021.12.10.)에서는 소위원회 검토 결과를 논의하여 의료기술재평가사업 관리지침 제4조 제10항에 의거 “방사선 온열치료 - 부인 종양”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 방사선 온열치료, 자궁경부암, 난소암, 안전성, 효과성

Hyperthermia Combined with Radiation Therapy—Gynecologic 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 gynecologic 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 gynecologic tumors?" Safety was assessed based on adverse events and reported toxicity associated with hyperthermia combined with radiation therapy, and effectiveness was assessed based on the overall survival (OS), disease-free survival (DFS), remission rate, local control rate, and local recurrence rate. 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

Cervical cancer Twelve articles (nine studies) on gynecologic tumors were finally selected for this assessment, which included studies on cervical cancer and ovarian cancer. Among them, 10 articles (seven studies) addressed cervical cancer, consisting of nine randomized controlled trials (RCTs; six studies) and one prospective cohort study. A total of 1,010 patients, with an average age ranging from 45 to 64.9 years across the studies, were included in the RCTs on cervical cancer. Hyperthermia was conducted at a temperature of 39.5–43℃, for 55–90 min, one to three times per week. The ROB was considered “high” due to selective reporting, incomplete outcome data, and private research fund support. One prospective cohort study on cervical cancer (Lee et al., 2017) was conducted in South Korea in patients with recurrent cervical cancer, which recurred after complete remission in primary treatment. The study included 38 patients with an average age of 50.8 years. The intervention involved hyperthermia combined with radiation therapy and/or chemotherapy, and hyperthermia was conducted at a temperature of 39.8–41.9℃ for 60 min/session, for three sessions per week. The ROB was considered to be uncertain for confounders and low for all other indicators.

Safety in cervical cancer patients Two studies (one RCT and one prospective cohort study) reported adverse events related to hyperthermia combined with radiation therapy. In the RCT, first to second degree fat layer burns occurred significantly more often in the intervention group treated with hyperthermia combined with radiation therapy (9.5%) than in the control group (1%) (p = 0.02), although there was no statistically significant difference between the two groups in terms of the follow-up results. The prospective cohort study reported the occurrence of adverse events only in the intervention group treated with hyperthermia combined with radiation therapy, without reporting the results in the control group. Hyperthermia-related late toxicity was not found in any patients, while abdominal discomfort and heat were reported in 44.4% of the patients. Toxicities were reported for other organs, such as the urinary system, gastrointestinal system, kidneys, blood, and skin, although there were no statistically significant differences in serious adverse events between the two groups. The Subcommittee determined that such organ-specific toxicities were adverse events from radiation therapy and/or chemotherapy, rather than being related to hyperthermia.

Effectiveness against cervical cancer The effectiveness of hyperthermia combined with radiation therapy was assessed based on the OS, DFS, remission rate, local control rate, and local recurrence rate as indicators. In the RCT, the intervention group using hyperthermia with radiation therapy and/or chemotherapy showed a 1.23-fold improvement in the complete remission rate as compared with the control group that used radiation therapy and/or chemotherapy (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.02–1.50, I2 = 0.0%). However, the meta-analysis revealed no statistically significant difference between the groups in terms of other indicators, such as the OS (RR 1.03, 95% CI 0.92–1.16, I2 = 0.0%), DFS (RR 1.14, 95% CI 0.82–1.59, I2 = 0.0%), local progression-free survival (LPFS; RR 1.10, 95% CI 0.96–1.25, I2 = 30.7%), partial remission rate (RR 0.73, 95% CI 0.51–1.05, I2 = 0.0%), stable disease (SD; RR 0.26, 95% CI 0.06–1.19, I2 = 0.0%), objective remission rate (RR 1.03, 95% CI 0.83–1.26, I2 = 0.0%), and distant metastasis rate (RR 0.87, 95% CI 0.37–1.60, I2 = 18.8%). In addition, some indicators that could not be meta-analyzed with only one case reported for each, such as the local control rate, pelvic tumor control rate, progressive disease (PD), local recurrence rate, and pelvic tumor recurrence rate, also showed no significant differences between the two groups. The single prospective cohort study on cervical cancer only reported that there was no significant difference in DFS between the two groups (p = 0.235). The remission rate was reported for the time points after completion of treatment and at the follow-up: the intervention group using hyperthermia with radiation therapy and/or chemotherapy showed a statistically significantly higher remission rate than the chemotherapy group.

Ovarian cancer The two studies on ovarian cancer included one RCT and one non-RCT (NRCT). The RCT on ovarian cancer was conducted in 48 patients with advanced ovarian cancer accompanied by severe ascites. The intervention involved hyperthermia combined with radiation therapy and/or chemotherapy. Hyperthermia was conducted at a temperature of 42.5–43℃ for 60 min/session, twice per week, for a total of eight sessions. The ROB was considered high due to selective reporting and incomplete outcome data. The NRCT on ovarian cancer was conducted in 73 patients with advanced ovarian cancer. The intervention involved hyperthermia combined with radiation therapy and/or chemotherapy, and hyperthermia was conducted at a temperature of 42.5–43.5℃ for 60–120 min/session, two to three sessions per week, for a total of eight sessions. The ROB was considered to be uncertain for allocation concealment and “low” for all other indicators.

Safety in ovarian cancer patients Among the studies on ovarian cancer, no study reported adverse events related to hyperthermia combined with radiation therapy. While overall toxicities, hematologic toxicities, and gastrointestinal toxicities were reported, no serious adverse events showed differences between the two groups. The Subcommittee determined that such organ-specific toxicities were adverse events from radiation therapy and/or chemotherapy rather than being related to hyperthermia.

Effectiveness against ovarian cancer The RCT on ovarian cancer reported a statistically significant improvement in the intervention group using hyperthermia with chemotherapy as compared with the chemotherapy control group in terms of local control rates (75% and 54.2%, respectively) and treatment responses (complete remission rates: 16.7% and 4.2%, respectively; partial remission rates: 33.3% and 20.8%, respectively; SD: 25% and 29.2%, respectively; PD: 25% and 45.8%, respectively) (all p < 0.05). There was no significant difference in OS between the groups (p = 0.672). In the NRCT on ovarian cancer, the intervention group using hyperthermia with chemotherapy demonstrated a significant improvement in the tumor remission rate (83.3% in the intervention group and 43.2% in the control group) as compared with the chemotherapy group (p < 0.05). The OS was 41.6% in the intervention group and 62.1% in the control group, although no results verifying the difference between the two groups were reported.

Conclusions and Recommendations

Cervical cancer This systematic literature review found that, in patients with cervical cancer, first or second degree burn and flushing occurred more often in the intervention group, suggesting that caution is required when using this intervention. However, considering that there was no increase in severe adverse events, it was assessed as being a safe technique. In terms of effectiveness, there was a statistically significant 1.23-fold improvement in the complete remission rate in the intervention group as compared with the control group, although no significant difference was found between the groups in terms of other indicators, such as the OS, DFS, LPFS, local control rate, pelvic control rate, partial remission rate, SD, PD, objective remission rate, local recurrence rate, pelvic tumor recurrence rate, and distant metastasis rate. As a result of this assessment, the Subcommittee determined that hyperthermia, with a controlled temperature, combined with radiation therapy and/or chemotherapy could be used as a safe technique in patients with cervical cancer. However, it was assessed as having no additional therapeutic effect as compared with radiation and/or chemotherapy (confidence level of evidence: moderate).

Ovarian cancer This systematic literature review on hyperthermia combined with radiation therapy and/or chemotherapy in patients with ovarian cancer found that no adverse events associated with hyperthermia and that the toxicities associated with chemotherapy (hematologic adverse events) showed no significant difference between the two groups. In terms of effectiveness indicators, the treatment response and local control rates were reported to be significantly improved in the intervention group using hyperthermia with chemotherapy as compared with the chemotherapy group, although there was no significant difference in OS between the two groups. Accordingly, as a result of this assessment, the Subcommittee determined that there was insufficient evidence for judging the safety and effectiveness of hyperthermia combined with radiation therapy and/or chemotherapy in patients with ovarian cancer based on only one RCT and one NRCT (confidence level of evidence: moderate). The 12th Health Technology Reassessment Committee in 2021 (December 10, 2021) reviewed hyperthermia combined with radiation therapy in patients with gynecologic 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 to radiation therapy and/or chemotherapy but that there was insufficient evidence or that additional therapeutic effects were not confirmed, even when evidence was provided, 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 and chemotherapy 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: Cervical cancer, Effectiveness, Hyperthermia treatment, Ovarian cancer, Safety