Factors With Inadequate Evidence of an Association With Colorectal Cancer

대장암과 관련된 부 적절한 증거의 요인들

Nonsteroidal anti-inflammatory drugs

비 스테로이드 성 항염증 약물

One large cohort study (301,240 people with 3,894 CRC cases) found an association between daily or weekly nonaspirin (non-ASA) nonsteroidal anti-inflammatory drug (NSAID) use and reduced 10-year incidence of proximal and distal colon cancer, but not rectal cancer, with an HR of 0.67 (95% CI, 0.58–0.77) for daily use for colon cancer. Because exposure to non-ASA NSAIDs was assessed only once, assessment was by self-report, and there is no information on dose or duration of use, the certainty of this single study must be rated low. Further research is needed before this finding can be accepted.[85]

한 대규모 코호트 연구(3,893명의 대장암 사례를 포함한 총 39,294명)에서 대장암이 아닌 사람, 대장암(비-ASA)이 일일 또는 주간 비 스테로이드 성 항염증 약물(NSAID) 사용과 직장암이 아닌, 근위 및 원위 결장암의 10년 발생률의 감소 간의 연관성을 발견하였다. 비-아세텔살리실 산 비 스테로이드 성 항염증 약물에 대한 노출은 단 한 번만 평가되었기 때문에, 평가는 자체 보고에 의한 것이었으며, 용량이나 사용 기간에 대한 정보가 없기 때문에 이 단일 연구의 확실성은 신뢰 등급이 낮아야 한다. 이 결과가 받아들여지려면 아직 더 많은 연구가 필요하다.

Although evidence is currently inadequate to determine whether NSAIDs reduce CRC incidence, proponents suggest that any effect of these drugs results from their ability to inhibit the activity of cyclooxygenase (COX). COX is important in the transformation of arachidonic acid into prostanoids, prostaglandins, and thromboxane A2. NSAIDs include not only aspirin (ASA, which is considered separately here) and other, first-generation nonselective inhibitors of the two functional isoforms of COX, termed COX-1 and COX-2, but also newer second-generation drugs that inhibit primarily COX-2. Normally, COX-1 is expressed in most tissues and primarily plays a housekeeping role (e.g., gastrointestinal mucosal protection and platelet aggregation). COX-2 activity is crucial in stress responses and in mediating and propagating the pain and inflammation that are characteristic of arthritis.[86]

NSAIDs가 대장암 발병률을 감소시키는지 여부를 판단하기에 증거가 현재로는 불충분하지만, 지지자들은 이러한 약물의 어떤 효과도 COX(사이클로옥시게나제)의 활동을 억제하는 그들의 능력에서 나온다고 말한다. COX는 아라키돈산을 프로스탄노이드와 프로스타글란딘 및 트롬복산 (혈소판에 함유되어 있는 혈액 응고에 관계되는 물질) A2로 변형시키는 데 중요하다. NSAID에는 아스피린(여기서 별도로 고려되는 ASA)과 1세대 비 선택적 COX 억제제(주로 COX-1, COX-2)뿐만 아니라 주로 COX-2를 억제하는 새로운 2세대 약물도 포함된다. 정상적으로 COX-1은 대부분의 조직에서 발현되며 주로 지킴이 역할(예를 들면, 위장 관 점막 보호 및 혈소판 집적)을 한다. COX-2 활동은 스트레스 반응과 관절염의 특징인 통증과 염증을 조정 및 전파하는데 중요하다.

Nonselective COX inhibitors include, indomethacin (Indocin); sulindac (Clinoril); piroxicam (Feldene); diflunisal (Dolobid); ibuprofen (Advil, Motrin); ketoprofen (Orudis); naproxen (Naprosyn); and naproxen sodium (Aleve, Anaprox). Selective COX-2 inhibitors include celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra). Rofecoxib and valdecoxib are no longer marketed because of an associated increased risk of serious cardiovascular events.

비 선택적 COX 억제제로는 인도메타신(상표명 : 인도신), 설린닥 (상표명 : 클리노릴), 피록시캄(상표명 : 펠덴), 디플루니살(상표명 : 돌로비드), 이부프로펜 (상표명 : 아드빌, 모트린), 케토프로펜 (상표명 : 오루디스), 나프록센 (상표명 ; 나프록신) 및 나프록센 소디움 (상표명 : 알레브, 아나프록스)이다.

선택적 COX-2 억제제로는 셀레콕시브(상표명 : 셀레브렉스), 로페콕시브(상표명 : 바이옥스), 발데콕시브(상표명 : 벡스트라) 등이 있다. 로페콕시브와 발데콕시브는 심각한 심혈관 질환의 위험이 증가와 관련성이 있기 때문에 더 이상 시판되지 않는다.

Both celecoxib and rofecoxib have been associated with serious cardiovascular events including dose-related death from cardiovascular causes, myocardial infarction, stroke, or heart failure.[87-90] Four trials that demonstrated this increased risk are summarized in the Table 1. In addition, a network meta-analysis of all large scale randomized, controlled trials (RCTs) comparing any NSAID to any other NSAID or placebo found that there is little evidence to suggest that any of the investigated drugs are safe in terms of cardiovascular effects. Naproxen seemed least harmful.[91]

셀레콕시브와 로페콕시브 공히 심혈관 질환, 심근경색, 뇌졸중 또는 심부전으로 인한 약의 용량 관련 사망을 포함한 심각한 심혈관 질환과 관련되어 있다. 위험의 증가를 입증하는 네 가지 시험의 결과는 표 1에 요약되어 있다. 또한 NSAID를 다른 NSAID 또는 위약과 비교한 모든 대규모 무작위 대조 시험(RCT)의 네트워크 메타 분석은 조사된 약물에 대한 안전한 효과를 제안할 증거가 거의 없다는 것을 발견했다. 나프록센은 덜 해로워 보였다.

Table 1. Cardiovascular Risks Associated With Celecoxib and Rofecoxib Dose/Drugs

표1. 셀레콕시브와 로페콕시브와 관련된 심혈관 계통의 위험

Other major harms from all NSAIDs are gastrointestinal bleeding and renal impairment. The incidence of reported major gastrointestinal bleeding events appears to be dose-related.[92]

모든 비 스테로이드 약물로부터 오는 다른 주요한 해악은 위장 출혈과 신장 손상이다. 보고된 주요 위장 출혈의 발병률은 용량과 관련이 있는 것으로 보인다.

Celecoxib reduces the incidence of adenomas; however, celecoxib does not have a clinical role in reducing the risk of sporadic CRC. Its long-term efficacy in preventing CRC has not been shown because of increased risk of cardiovascular events, and because there are other effective ways, such as screening to reduce CRC mortality.[93] A population-based retrospective cohort study of nonaspirin NSAID use among individuals aged 65 years and older was associated with lower risk of CRC, particularly with longer durations of use.[94]

셀레콕시브는 선종 발생을 감소시키지만, 셀레콕시브는 산발적인 대장암의 위험을 줄이는 임상적 역할을 하지 않는다. 대장암을 예방하는 데 있어 약의 장기 유효성은 심혈관 질환의 위험 증가와 대장암 사망률을 줄이기 위한 검사와 같은 다른 효과적인 방법들이 있기 때문에 나타나지 않았다. 65세 이상의 개인들 사이의 비-아스피린 NSAID 사용에 대한 모집단 기반 소급 코호트 연구는 대장암의 낮은 위험, 특히 장기간의 사용과 관련이 있었다.

Several rigorous studies have demonstrated the effectiveness of sulindac in reducing the size and number of adenomas in familial polyposis.[95,96] In a randomized, double-blind, placebo-controlled study of 77 patients with FAP, patients receiving 400 mg of celecoxib twice a day had a 28.0% reduction in the mean number of colorectal adenomas (P = .003 for the comparison with placebo) and a 30.7% reduction in the polyp burden (sum of polyp diameters; P = .001) as compared with reductions of 4.5% and 4.9%, respectively, in the placebo group. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9% (P = .33 for the comparison with placebo) and 14.6% (P = .09), respectively. The incidence of adverse events was similar among the groups.[97]

몇몇 엄격한 연구들은 가족성 용종증의 선종의 크기와 수를 줄이는데 있어서 설린닥의 효과를 입증했다. 가족성 선종 용종증(FAP)을 가진 77명의 환자들에 대한 무작위, 이중 블라인드, 위약 대조군 연구에서, 하루에 두 번 400mg의 셀레콕시브를 받는 환자들은 평균 대장 선종의 수의 감소가 28.0%, 용종 존재량(용종 직경의 합)의 감소가 30.7%였고, 이에 비해. 위약 그룹에서 각각 4.5%, 4.9%였다. 하루에 두 번 100mg의 셀레콕시브를 받은 그룹의 감소는 각각 11.9%(위약과의 비교의 경우 P = 0.33)와 14.6%(P = 0.09)이었다. 부작용 발생은 그룹 간에 유사했다.

The NSAID piroxicam, at a dose of 20 mg/day, reduced mean rectal prostaglandin concentration by 50% in individuals with a history of adenomas.[98] Several studies assessing the effect of ASA or other nonsteroidals on polyp recurrence following polypectomy are in progress.[99] In several of these studies, mucosal prostaglandin concentration is being measured.

NSAID 피록시캠은 하루에 20mg씩 복용했을 때 선종 이력을 가진 개인의 평균 직장直腸의 프로스타글란딘(생체 내에서 합성된 생리활성물질) 농도를 50% 감소시켰다. 용종절제술 이후 ASA 또는 기타 비 스테로이드제가 폴립 재발을 위해 미치는 영향을 평가하는 여러 연구가 진행 중이다. 이러한 연구들 중 몇 가지에서는 점막 프로스타글란딘 농도가 측정 중이다.

The potential for use of NSAIDs as a primary prevention measure is being studied. There are, however, several unresolved issues that preclude making general recommendations for their use. These include a paucity of knowledge about the proper dose and duration for these agents, and concern about whether the potential preventive benefits such as a reduction in the frequency or intensity of screening or surveillance could counterbalance long-term risks such as gastrointestinal ulceration and hemorrhagic stroke for the average-risk individual.[100]

주요 예방 조치로 비 스테로이드계 약물(NSAID)을 사용할 가능성이 있는지 연구되고 있다. 그러나 이러한 용도로 사용할 수 있는 일반적인 권장 사항을 제시하지 못하는 몇 가지 해결되지 않은 문제가 있다. 여기에는 이러한 약물에 대한 적절한 용량과 지속 기간에 대한 지식이 부족할 뿐 아니라, 선별이나 감시의 빈도나 강도 감소와 같은 잠재적 예방 이익이 평균 위험군 개인들의 위장관의 궤양과 출혈성 뇌졸중 같은 장기적 위험과 균형을 이룰 수 있는지에 대한 우려가 포함된다.

Calcium supplements

칼슘의 보충

A randomized placebo-controlled trial tested the effect of calcium supplementation (3 g calcium carbonate daily [1,200 mg elemental calcium]) on the risk of recurrent adenoma.[101] The primary endpoint was the proportion of patients (72% of whom were male) in whom at least one adenoma was detected following a first and/or second follow-up endoscopy. A modest decrease in risk was found for both developing at least one recurrent adenoma (adjusted risk ratio [ARR], 0.81; 95% CI, 0.67–0.99) and in the average number of adenomas (ARR, 0.76; 95% CI, 0.60–0.96). The investigators found the effect of calcium was similar across age, sex, and baseline dietary intake categories of calcium, fat, or fiber. The study was limited to individuals with a recent history of colorectal adenomas and could not determine the effect of calcium on risk of the first adenoma, nor was it large enough or of sufficient duration to examine the risk of invasive CRC. After calcium supplementation is stopped, the lower risk may persist up to 5 years.[102] The results of other ongoing adenoma recurrence studies are awaited with interest. It is important to note that the dose of calcium salt administered may be important; the usual daily doses in trials have ranged from 1,250 to 2,000 mg of calcium.

한 무작위 위약-대조군 임상시험에서 칼슘 보충(매일 탄산칼슘 3g [1,200mg 원소 칼슘])이 재발 선종 위험에 미치는 효과를 시험하였다.

주된 연구의 목표는 첫 번 및/혹은 두 번째 내시경 검사에서 최소한 한 개의 선종이 발견되는 환자(환자의 72%는 남성)의 비율을 찾는 것이었다. 최소한 한 개의 선종의 발병과 선종의 평균 개수 두 가지 면에서 공히 위험의 미세한 감소가 있었다. 연구자들은 칼슘의 영향이 나이와 성별, 그리고 칼슘과 지방, 섬유질의 기본 식이 섭취 범주를 통 털어서 비슷하다는 것을 발견했다. 이 연구는 최근의 대장 선종의 병력을 가진 개인들로 제한되었고 첫 번째 선종 위험에 대한 칼슘의 영향을 알아낼 수 없었고, 침습성 대장암의 위험을 검사하기에 충분히 규모가 크거나 시간적으로 충분히 길지 않았다. 칼슘 보충이 중단된 후에도 낮아진 위험은 최대 5년까지 지속될 수 있다.

현재 진행 중인 다른 선종 재발 연구의 결과를 관심을 갖고 기대하고 있다. 투여된 칼슘염의 용량이 중요할 수 있다는 점을 유념하는 것이 중요하다. 즉 시험 중 투여된 일상적인 일일 사용량의 범위는 1,250에서 2,000mg 사이이다.

In a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women, the administration of 500 mg of elemental calcium and 200 IU of vitamin D3 twice daily for an average of 7.0 years was not associated with a reduction in invasive CRC (HR, 1.08; 95% CI, 0.86–1.34; P = .051).[103] The relatively short duration of follow-up, considering the latency period of CRC of 10 to 15 years, and suboptimal doses of calcium and vitamin D, may account for the negative effects of this trial, although other factors may also be responsible.[104]

36,282명의 폐경기 여성을 대상으로 한 무작위 이중 맹검 위약 대조군 실험에서, 평균 7년간, 칼슘(원소) 500mg과 비타민 D3 200 IU를 하루 두 번 투여해도 침습성 대장암의 감소와는 별 상관이 없었다. 다른 요인들도 그 원인이기는 하지만, 10년에서 15년의 잠복기간과 칼슘과 비타민 D의 부 최적 용량을 고려할 때 상대적으로 짧은 추적 기간이 이 임상시험의 부정적인 효과의 원인이라 할 수 있다.

Dietary factors

식이요인

Dietary fat and meat intake

식사를 통한 지방과 육류의 섭취

Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat.[105] On average, fat comprises 40% to 45% of total caloric intake in high-incidence Western countries; in low-risk populations, fat accounts for only 10% of dietary calories.[106] In laboratory studies, a high-fat intake increases the incidence of induced colon tumors in experimental animals.[107,108] Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake.[12,109] Although positive associations with meat consumption or with fat intake have been found frequently, the results have not always achieved statistical significance.[110] A number of prospective cohort studies have been conducted in the United States and abroad. In Japan, an increased risk of colon cancer with increased frequency of meat consumption was observed in the group with infrequent vegetable consumption among a group of 265,000 men and women.[111] In Norway, an increased risk for processed meat only was found,[112] a finding that was confirmed in the Netherlands.[113] A clearly defined gradient in the risk for frequency of meat and poultry consumption was not observed in a population of Seventh Day Adventists that included a large proportion of vegetarians.[114] A prospective study among female nurses showed an increased risk of colon cancer associated with red meat consumption (beef, pork, lamb, and processed meat) and also with the intake of saturated and monounsaturated fat, predominantly derived from animals.[115] In two other large prospective studies, the CPS II and the Iowa Women’s Health Study (IWHS), no increase in the risk of colon cancer was seen with meat or fat consumption.[116,117] In a prospective cohort study of a low-risk population of non-Hispanic white members of the Adventist Health Study, a positive association between meat (both red and white) intake and colon cancer was observed (RR for ≥1 time per week vs. no meat intake, 1.85; 95% CI, 1.19–2.87; P for trend = .01).[118] It has been hypothesized that the heterocyclic amines (HCAs) formed when meat and fish are cooked at high temperatures may contribute to the increased risk of CRCs associated with meat consumption that has been observed in epidemiologic studies. A population-based case-control study in Sweden, however, found no evidence of increased risk associated with total HCA intake; for colon cancer the RR was 0.6 (95% CI, 0.4–1.0), and for rectal cancer it was 0.7 (95% CI, 0.4–1.1).[119,120]

대장암 발병률은 총 지방 섭취량이 높은 인구 집단에서 높으며 지방을 적게 소비하는 인구 지단에서 낮다. 평균적으로, 발병률이 높은 서유럽 국가에서는 지방이 총 열량 섭취의 40%에서 45%로 구성되어 있고, 저 위험 인구 집단에서는 지방은 식사 칼로리의 단지 10%밖에 안 된다. 실험실 연구에서, 고 지방 섭취는 실험용 동물에서도 유발 대장 종양의 발생률을 증가시킨다. 몇몇 사례-대조군 연구에서 단백질과 에너지 섭취뿐만 아니라 고기 또는 지방 소비와 대장암 위험과의 연관성을 연구하였다. 육류 소비나 지방 섭취와 관련된 긍정적인 연관성이 자주 발견되기는 했지만, 그 결과는 항상 통계적 의미를 얻지는 못했다. 미국과 해외에서 많은 전향적 코호트 연구가 수행되었다. 일본에서 265,000명의 남성과 여성 그룹 중 야채 소비의 빈도가 낮은 그룹에서 고기의 섭취 빈도가 높아지면서 대장암 발병률이 증가하였다. 노르웨이에서는 가공육에 대한 위험만 증가하였지만, 이 결과는 네덜란드에서도 확인되었다. 육류 및 가금류 소비의 빈도로 인한 위험에서 명확하게 이것이라 지명할 수 있는 재료는 많은 수의 채식주의자들이 포함된 제7일 안식일 예수 재림교에서는 관찰되지 않았다.

여성 간호사의 전향적 연구에서 붉은색 육류 소비(소고기, 돼지고기, 양고기 및 가공육)와 주로 동물에서 채취한 포화 지방과 불포화 지방의 섭취와 관련된 대장암의 위험이 증가했음을 보여주었다. 다른 두 개의 대규모 후향적 연구와 CPS II 및 아이오와 여성 건강 연구(IWHS)에서는 대장암의 위험 증가가 육류나 지방 섭취에서는 보이지 않았다. 말일성도 건강연구의 비 히스패닉 백인 교인의 저 위험 모집단에 대한 사전 코호트 연구에서 육류 (붉은색 및 흰색 공히) 섭취와 대장암 사이의 양성 연관성이 관찰되었다. 육류와 어류가 고온에서 요리될 때 형성된 이종 환식 아민(HCA)이 역학 연구에서 관찰된 육류 소비와 관련된 대장암의 위험 증가에 기여했다고 가정하였다. 그러나 스웨덴의 인구 기반 환자-대조군 연구에서 총 HCA 섭취와 관련된 위험 증가의 증거를 찾지 못했고, 대장암의 경우 상대 위험은 0.6, 직장암의 경우 0.7이었다.

A randomized controlled dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the WHI. The intervention promoted a goal of reducing total fat intake by 20%, while increasing daily intake of vegetables, fruits, and grains. The intervention group accomplished a reduction of fat intake of approximately 10% more than did the comparison group during the 8.1 years of follow-up. There was no evidence of reduction in invasive CRCs between the intervention and comparison groups with a HR of 1.08 (95% CI, 0.90–1.29).[121] Likewise, there was no benefit of the low-fat diet on all-cancer mortality, overall mortality, or cardiovascular disease.[122]

여성건강계획에 등록된 50세에서 79세 사이의 폐경 후 여성 48,835명의 무작위 식단 수정 임상시험이 행해졌다. 개입을 통해 매일 야채와 과일, 곡물의 섭취를 증가시키는 동시에 총 지방 섭취를 20%까지 줄이는 목표를 촉진시켰다. 개입 그룹은 8.1년의 추적 기간 동안 대조군보다 지방 섭취를 약 10% 더 줄일 수 있었다. 위험 비율이 1.08(95% CI, 0.90–1.29)인 개입 그룹과 비교 그룹 사이에 침습성 대장암의 감소의 증거가 없었다. 마찬가지로, 전체 암 사망률, 전체 사망률 또는 심혈관 질환에 대한 저지방 식단의 이점도 없었다.

Explanations for the conflicting results regarding whether dietary fat or meat intake affects the risk of CRC [113] include:

식이 지방 또는 육류 섭취가 대장암의 위험에 영향을 미치는지에 대한 상충되는 결과에 대한 설명은 다음을 포함한다.

•Validity of dietary questionnaires used.

사용된 식이 설문조사의 타당성

•Differences in the average age of the population studied.

연구 대상의 평균 연령의 차이

•Variations in methods of meat preparation (in some instances, mutagenic and carcinogenic HCAs could have been released at high temperatures).[123]

육류 준비 방법(일부 예를 들면, 돌연변이성 및 암 성 HCA가 고온에서 분비될 수 있다) 상의 다양성

•Variability in the consumption of other foods such as vegetables.[124]

야채와 같은 다른 식품의 소비의 가변성

Six case-control studies and two cohort studies have explored potential dietary risk factors for colorectal adenomas.[22,125] Three of the eight studies found that higher fat consumption was associated with increased risk. High fat intake has been found to increase the risk of adenoma recurrence following polypectomy.[126] In a multicenter RCT, a diet low in fat (20% of total calories) and high in fiber, fruits, and vegetables did not reduce the risk of recurrence of colorectal adenomas.[127]

6건의 환자-대조군 연구와 2건의 코호트 연구에서 대장선종에 대한 잠재적 식이 요법 위험 인자를 조사했다. 8건의 연구 중 3건에서 높은 지방 섭취가 위험 증가와 관련이 있다는 것을 발견했다. 고지방 섭취는 용종 절제술 후 선종의 재발 위험을 증가시키는 것으로 밝혀졌다. 복수 센터의 무작위 대조군 임상시험에서 지방 함량이 낮고 섬유질, 과일, 야채 함량이 높은 식단은 대장선종의 재발 위험을 줄이지 않았다.

Thus, the evidence is inadequate to determine whether reducing dietary fat and meat would reduce CRC incidence.

따라서 그 증거는 식이 지방과 고기를 줄이는 것이 CRC 발생을 감소시킬지 여부를 알아내기에 불충분하다.

Factors and Interventions With Adequate Evidence of no Association With Colorectal Cancer

대장암과 무관하다는 적절한 증거를 가진 요인과 개입

Estrogen-only therapy

에스트로겐 단독 요법

The estrogen-only intervention component of the WHI was conducted among women who had a hysterectomy, with CRC incidence included as a secondary trial endpoint. CRC incidence was not decreased among women who had taken estrogens; after a median of 7.1 years of follow-up, 58 invasive cancers occurred in the estrogen arm compared with 53 invasive cancers in the placebo arm (HR, 1.12; 95% CI, 0.77–1.63). Tumor stage and grade were similar in the two groups; deaths after CRC were 34% in the hormone group compared with 30% in the placebo group (HR, 1.34; 95% CI, 0.58–3.19).[128]

「여성건강계획의 에스트로겐 단독 개입 요소를 자궁절제술을 받은 여성들 에게 시술했고, 대장암 발병률은 2차 시험 목표로 포함되었다. 대장암 발병률은 에스트로겐을 복용한 여성들 사이에서 감소하지 않았다. 중앙값 7.1년의 추적 치료 후, 플라시보 그룹에서 53건의 침습암 발병에 비해 에스트로겐 그룹에서는 58건의 침습암 이 발병하였다. 종양의 병기와 등급은 두 그룹에서 유사했다. 위약 그룹의 30%와 비교하여 호르몬 그룹의 대장암 후 사망률은 34%였다.

Statins

스타틴

Overall, evidence indicates that statin use neither increases nor decreases the incidence or mortality of CRC. Although some case-control studies have shown a reduction in risk, neither a large cohort study [129] nor a meta-analysis of four RCTs [130] found any effect of statin use.

종합하면, 스타틴의 사용이 대장암의 발병이나 사망률을 증가나 감소도 시키지 않는다는 것을 증거가 입증하였다. 일부 사례-대조군 연구는 위험의 감소를 보여주었지만, 대형 코호트 연구 [129] 또는 4개의 무작위 대조군 시험에 대한 메타 분석결과를 보면, 스타틴 사용의 어떤 영향도 발견하지 못했다.

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