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 소화기종양 환자에서 방사선 온열치료의 임상적 안전성 및 효과성 등에 대한 과학적 근거를 제공하고 이를 통해 의료기술의 적정사용 등 정책적 의사결정을 지원하는 것이다.

평가 방법

비뇨기종양 환자에서 방사선 온열치료에 대한 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 “방사선 온열치료 소위원회(이하 ‘소위원회’)”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 “비뇨기종양 환자에서 방사선 또는 항암요법과 병행하는 온열치료는 임상적으로 안전하고 효과적인가?”이었고, 안전성은 온열치료 관련 이상반응과 보고된 독성을 결과지표로 하였고, 효과성은 생존율, 관해율 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 Assessment, Development and Evaluation (GRADE) 방법을 이용하여 근거 수준을 평가하고, 평가 결과를 토대로 권고등급을 결정하였다.

평가 결과

평가주제와 관련된 문헌을 찾기 위해 국내외 전자데이터베이스를 사용하여 검색하였으며 방사선 온열치료과 관련하여 총 44편의 문헌이 선택되었다. 비뇨기 종양으로 최종 선택된 문헌은 3편이었으며 방광암 2건편, 전립선암 1편이었다. 

방광암 

방광암에서 최종 선택된 문헌은 무작위배정임상연구(Randomized controlled trial, RCT) 1편, 비무작위배정연구(Non-randomized controlled trial, NRCT) 1편이었다. 연구수행국가는 네덜란드, 독일을 포함한 유럽 2개국이었다. 

RCT 연구는 방광암 환자 101명을 대상으로 진행되었으며 연령 중앙값은 방사선 및 온열치료을 수행하는 중재군에서 73세, 방사선요법만을 수행하는 비교군은 69세이었다. 온열치료의 온도는 42℃였으며 주 1회 60~90분 동안 총 5회 수행하였다. NRCT 연구는 고위험 표재성 및 근육 침육성 방광암 환자 294명을 대상으로 하였으며 연령 중앙값은 66~67세이었다. 방사선화학요법과 온열치료의 병행요법과 방사선 및 화학요법을 비교하였다. 온열치료는 41.5도에서 60~90분 동안 주1회, 중앙값 총 5회 수행되었다. 

방광암 안전성

1편의 연구에서 안전성 보고를 하였다. 온열치료와 직접적으로 관련된 이상반응은 보고되지 않았다. 비뇨기계 독성과 관련하여 3, 4등급 방광독성은 중재군에서 각각 4편(5%), 1편(1.3%) 보고되었으며 비교군에서는 각각 13편(6%), 4편(1.9%) 보고하였다. 방광절제술은 중재군에서 1편(1.3%), 비교군에서 5편(2.3%) 발생하였다. 후기 독성으로 4등급 방광수축이 중재군에서 2편(2.5%), 비교군에서 11편(5.1%) 발생하였다. 3, 4등급의 급성 설사 독성은 중재군에서 17편(21%), 비교군에서 35편(16%) 발생하였고 2등급 후기 중등도의 설사는 중재군에서 7편(8.9%), 20편(9.3%) 발생하였으며 통계적 유의성은 보고하지 않았다. 4등급 백혈구 감소증은 중재군에서 2편(3%), 비교군에서 12편(6%) 발생하였으며 혈소판 감소증은 중재군 및 비교군에서 각각 1편(1%), 4편(2%) 발생하였으며 방사선화학요법과 관련성이 있는 것으로 소위원회는 판단하였다. 

방광암 효과성

온열치료 효과성은 생존율, 관해율 관련 결과지표로 평가하였다. 

1편의 RCT에서 보고한 3년 전체 생존율은 중재군 72%, 비교군 78%로 군 간 유의성이 없었으나(p=0.33) 완전 관해율은 중재군 73.1%, 비교군 51.0%로 온열치료 병용으로 향상됨을 확인하였다(p=0.01). 

NRCT에서 보고한 5년 전체 생존율은 중재군 87% (95% confidence interval (CI) 79~95%), 비교군 64% (95% CI 58~71%)이었고 위험비(Hazard Ratio, HR)는 0.46 (95% CI 0.27~0.78)로 중재군의 전체 생존율이 더 높았다(p=0.004). 5년 무질병 생존율도 중재군과 비교군에서 각각 66% (95% CI 55~78%), 40% (95% CI 34~47%)이고 HR 값은 0.56 (95% CI 0.37~0.85)으로 온열치료와의 병용중재로 방사선화학요법 단독치료군보다 무질병 생존율이 유의하게 증가하였다(p=0.006). 무방광절제술 생존율의 HR 값은 0.13 (95% CI 0.03~0.56)으로 온열치료와 방사선화학요법을 수행한 병용군이 방사선 및 화학요법만을 수행한 비교군보다 방광보존율이 유의하게 높았다(p=0.006).

전립선암 

전립선암에서 온열치료를 병용중재한 연구는 총 1편 선택되었다. 연구수행국가는 일본이었으며 고위험 및 초고위험 전립선암 환자 146명을 대상으로 연구하였다. 환자의 연령은 50~72세가 중재군에서 65%, 비교군에서 48%이었으며 중재치료는 방사선요법과 온열치료의 병용치료였다. 비뚤림위험을 평가한 결과, 배정순서은폐에 대한 언급이 없어 ‘불확실’로 평가하였으며 그 외 비뚤림위험은 ‘낮음’으로 확인하였다.

전립선암 안전성

전립선암에서 최종 선정된 NRCT 1편의 연구에서 온열치료 관련 이상반응은 보고되지 않았다. 2등급 또는 3등급의 급성 및 후기 비뇨생식기 독성이 발생하였으나 중재군과 비교군 간 통계적으로 유의한 차이는 없었다. 또한 급성 및 후가 위장관 독성도 보고하였지만 군 간 차이는 없었다.

전립선암 효과성

온열치료 효과성은 생존율, 관해율 관련 결과지표로 평가하였다. 중재군과 비교군을 통합한 전체 환자에서의 5년 전체 생존율은 97%이었다. 5년 무진행 생존율은 중재군에서 82%, 비교군에서 81%로 군 간 유의한 차이가 없었으며(p=0.30), 무원격전이 생존율 역시 군 간 유의한 차이는 없었다(p=0.63).

결론 및 제언

방광암 

방광암에서 방사선요법 또는 방사선화학요법과 온열치료의 병용치료에 대한 체계적 문헌고찰을 수행한 결과, 온열치료와 직접적으로 관련이 있는 이상반응은 보고되지 않았으며 3~4등급의 비뇨기계 독성(방광독성, 방광절제술, 장폐색)은 비교군에서 더 높았으나 통계적 유의성은 보고되지 않았다. 그 외 위장관계, 혈액학 독성의 발생이 보고되었다. 효과성의 경우, 1편의 RCT에서 보고된 전체 생존율은 중재군과 비교군 간에 차이가 없었으나 완전 관해율은 온열치료 병용중재군에서 유의하게 높았다. NRCT 1편에서 보고한 전체생존율, 무질병생존율은 온열치료 병용중재군에서 비교군 대비 유의한 개선효과를 나타내었다.

본 평가결과, 방광암에서 방사선요법 또는 방사선화학요법과 온열치료 병용요법에 대한 문헌이 RCT 1편, NRCT 1편으로 소위원회에서는 온열치료 병용요법에 대한 안전성과 효과성을 판단하기에 근거가 불충분한 것으로 평가하였다(근거의 신뢰수준, Very low ~ Moderate).

전립선암 

전립선암에서 방사선요법과 온열치료의 병용요법에 대한 체계적 문헌고찰을 수행한 결과, NRCT 1편의 문헌이 선택되었다. 안전성 결과, 온열치료 관련 이상반응은 보고되지 않았으며 양 군간 비뇨기계 및 위장관계 독성 발생에 차이가 없었다. 효과성 지표에서 전체생존율, 무진행 생존율 모두 온열치료 병용에 따른 유의한 차이는 없었다.

본 평가결과, 소위원회에서는 전립선암에서 방사선요법과 온열치료 병용중재는 선택문헌이 NRCT 1편으로 안전성과 효과성을 판단하기에 근거가 불충분한 것으로 평가하였다(근거의 신뢰수준, Low).

2021년 제12차 의료기술재평가위원회(2021.12.10.)에서는 소위원회 검토 결과와 관련하여 논의를 하여 의료기술재평가사업 관리지침 제4조제10항에 의거 “비뇨기종양 환자에서의 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, 방광암, 전립선암, 효과성, 안전성 

Induced hyperthermia, Unrinary bladder neoplasms, Prostatic neoplasms, Effectiveness, Safety

Hyperthermia Combined with Radiation Therapy—Urologic 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 urologic 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 urologic tumors?" Safety was assessed based on adverse events and reported toxicity associated with hyperthermia, and effectiveness was assessed based on the survival and remission rates. 

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

Domestic and foreign electronic databases were searched for reports on the topic, and 44 studies related to hyperthermia combined with radiation therapy were identified. Three studies on urologic tumors were finally selected, including two on urinary bladder neoplasms and one on prostatic neoplasms. 

Urinary bladder neoplasms 

The finally selected studies on urinary bladder neoplasms included one randomized controlled trial (RCT) and one non-RCT (NRCT), which had been conducted in the Netherlands and German. 

The RCT was conducted in 101 bladder cancer patients. The median age was 73 years in the intervention group receiving hyperthermia combined with radiation therapy and 69 years in the control group receiving radiation therapy alone. Hyperthermia was conducted at a temperature of 42℃ for 60–90 min, once a week, for five times in total. The NRCT was conducted in 294 patients with high-risk superficial and muscle-invasive bladder cancer. The median age was 66–67 years. Hyperthermia combined with radiation therapy and/or chemotherapy was compared with radiation therapy and/or chemotherapy. Hyperthermia was performed once a week for 60–90 min at 41.5℃, for a median of five times. 

Safety in urinary bladder neoplasm patients

One study reported the safety of the therapy in urinary bladder cancer patients. There were no adverse events directly associated with hyperthermia. In terms of urinary toxicity, grade 3 and 4 bladder toxicities were reported in four (5%) and one case(s) (1.3%), respectively, in the intervention group, and 13 (6%) and four cases (1.9%), respectively, in the control group. Cystectomy was performed in one case (1.3%) in the intervention group and in five (2.3%) in the control group. In terms of late toxicity, grade 4 bladder contractions occurred in two cases (2.5%) in the intervention group and in 11 (5.1%) in the control group. Grade 3 and 4 acute diarrheal toxicities occurred in 17 cases (21%) in the intervention group and in 35 (16%) in the control group, while grade 2 late moderate diarrhea occurred in seven cases (8.9%) and in 20 (9.3%), respectively, with no statistically significant differences reported. Grade 4 leukopenia occurred in two cases (3%) in the intervention group and in 12 (6%) in the control group, and thrombocytopenia occurred in one case (1%) in the intervention group and in four (2%) in the control group, which was determined by the Subcommittee to be associated with radiation therapy and chemotherapy.

Effectiveness against urinary bladder neoplasms

The effectiveness of hyperthermia was assessed based on the survival rate and remission rate-related indices. The 3-year overall survival (OS) reported by one RCT was 72% in the intervention group and 78% in the control group, with no significant differences between the groups (p = 0.33). The complete remission rate was 73.1% in the intervention group and 51.0% in the control group, confirming that the addition of heat treatment improved remission (p = 0.01). 

The 5-year OS reported by the NRCT was 87% in the intervention group (95% confidence interval [CI] 79–95%) and 64% in the control group (95% CI 58–71%). The hazard ratio (HR) was 0.46 (95% CI 0.27–0.78). OS was significantly higher in the intervention group (p = 0.004). The 5-year DFS was 66% (95% CI 55–78%) in the intervention group and 40% (95% CI 34–47%) in the control group. The HR was 0.56 (95% CI 0.37–0.85). Thus, combination therapy with hyperthermia significantly increased the DFS as compared with treatment with radiation therapy and/or chemotherapy alone (p = 0.006). The HR for survival rate without radical cystectomy was 0.13 (95% CI 0.03–0.56). The bladder preservation rate was significantly higher in the combination therapy group that received hyperthermia with radiation therapy and/or chemotherapy than in the control group that received radiation therapy and/or chemotherapy alone (p = 0.006).

Prostatic neoplasms 

One study on prostatic neoplasms applied hyperthermia with radiation therapy and/or chemotherapy. The study was conducted in Japan, with 146 high-risk and very-high-risk patients with prostatic neoplasms. In terms of age, patients aged 50–72 years accounted for 65% of the intervention group and 48% of the control group, where the intervention involved hyperthermia combined with radiation therapy. There was no mention of allocation concealment, such that ROB was assessed as uncertain, while the ROB was assessed as “low” for all other indicators.

Safety in prostatic neoplasm patients

No adverse events associated with hyperthermia were reported in the single NRCT on prostatic neoplasms finally included in the review. Grade 2 or 3 acute and late genitourinary toxicities occurred, although there was no statistically significant difference between the intervention and control groups. Acute and late gastrointestinal toxicities were also reported, although there were no significant differences between the groups.

Effectiveness against prostatic neoplasms

The effectiveness of hyperthermia was assessed based on the survival rate and remission rate-related indices. The 5-year OS for all patients, including the intervention and control groups, was 97%. The 5-year PFS was 82% in the intervention group and 81% in the control group, which was not significantly different (p = 0.30). There was also no significant difference in distant metastasis-free survival between the groups (p = 0.63).

Conclusions and Recommendations

Urinary bladder neoplasms 

This systematic literature review on hyperthermia combined with radiation therapy and/or chemotherapy in patients with urinary bladder neoplasms found no adverse events directly associated with hyperthermia. While the frequency of grade 3 and 4 urinary toxicities (cytotoxicity, cystectomy, and ileus) was higher in the control group, no statistically significant difference between the groups was reported. Other gastrointestinal and hematological toxicities were also reported. In terms of effectiveness, the OS reported in the single RCT included did not differ between the intervention and control groups, although the complete remission rate was significantly higher in the intervention group using combination therapy with hyperthermia. The OS and DFS reported in the one included NRCT indicated a significant improvement in the intervention group treated using combination therapy with hyperthermia, as compared with the control group.

As a result of this assessment, the Subcommittee determined that there was not enough evidence for judging the safety and effectiveness of hyperthermia combined with radiation therapy and/or chemotherapy in patients with urinary bladder neoplasms based on only one RCT and one NRCT included in the literature review (confidence level of evidence: very low to moderate).

Prostatic neoplasms 

This systematic literature review on hyperthermia combined with radiation therapy and chemotherapy in patients with prostatic neoplasms involved only one NRCT. In terms of safety, no adverse reactions related to hyperthermia were reported, with no difference in the incidence of urinary and gastrointestinal toxicities between the two groups. The indices for effectiveness, based on OS and PFS, did not show a significant difference following the use of hyperthermia.

As a result of this assessment, the Subcommittee determined that there was not enough evidence for judging the safety and effectiveness of hyperthermia combined with radiation therapy in patients with prostatic neoplasms based on only one NRCT (confidence level of evidence: low).

The 12th Health Technology Reassessment Committee in 2021 (December 10, 2021) reviewed "hyperthermia in patients with urologic 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 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, Prostatic neoplasms, Safety, Urinary bladder neoplasms

요약문 (국문) i

Ⅰ. 서론 1

  1. 평가배경 1

  2. 평가목적 10

Ⅱ. 평가 방법 11

  1. 체계적 문헌고찰 11

    1.1 개요 11

    1.2 핵심질문 11

    1.3 문헌검색 12

    1.4 문헌선정 13

    1.5 비뚤림위험 평가 13

    1.6 자료추출 14

    1.7 자료합성 14

    1.8 근거수준 평가 14

  2. 권고등급 결정 15

Ⅲ. 평가결과 16

  1. 문헌선정 결과 16

    1.1. 문헌선정 개요 16

  2. 방광암 17

    2.1. 선택문헌 특성 17

    2.2. 비뚤림위험 평가 결과 19

    2.3. 분석 결과 21

    2.4. GRADE 근거 평가 25

  3. 전립선암 27

    3.1. 선택문헌 특성 27

    3.2. 비뚤림위험 평가 결과 28

    3.3. 분석 결과 29

    3.4. GRADE 근거 평가 31

Ⅳ. 결과요약 및 결론 33

  1. 평가 결과 요약 33

    1.1 방광암 33

    1.2 전립선암 34

  2. 결론 34

    1.1 방광암 34

    1.2 전립선암 34

Ⅴ. 참고문헌 36

Ⅵ. 부록 37

  1. 의료기술재평가위원회 37

  2. 소위원회 38

  3. 문헌검색현황 39

  4. 비뚤림위험 평가 및 자료추출 양식 44

  5. 최종선택문헌 47