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The Emperor of ALL Maladies①

The Emperor of ALL Maladies①



It’s hard to imagine that the phenomenon of overdiagnosis could apply to cancer. Physicians and the public have all been taught the basic facts about cancer. It’s a horrible disease. It relentlessly spreads throughout the body. It invariably leads to death if not treated, and all too frequently even if it is treated. And the best way to treat it is to catch it early. So our goal as physicians is simple: find as many early cancers as possible.


Until a few years ago, it was medical heresy to suggest anything else.    H.GILBERT WELCH


By the early 1990s, cancer biologists could begin to model the genesis of cancer in terms of molecular changes in genes.To understand that model, let us begin with a normal cell, say a lung cell that resides in the left lung of a forty-year-old fire- safety-equipment installer. One morning in 1968, a minute silver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the silver with an inflammation. The cells around the silver begin to divide furiously, like a minuscule wound trying to heal, and a small clump of cells derived from the original cell arises at the side.


In one cell in that clump an accidental mutation occurs in the ras gene. The mutation creates an activated version of ras. The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which uncontrolled cell division has partly been unleashed cancer’s primordial ancestor.


A decade passes. The small collection of ras –mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of ras-mutated cells. A cell in this clump acquires a second mutation in its genes, activating a second oncogene.


Another decade passes. Yet another cell in that secondary mass of cells is caught in the path of an errant X-ray and acquires yet another mutation, this time inactivating a tumor suppressor gene. This mutation has little effect since the cell possesses a second copy of that gene, But in the next year. Another mutation inactivates the second copy of the tumor suppressor gene. Creating a cell that possesses two activated oncogenes and an inactive tumor suppressor gene.


Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood vessels to grow; another mutation within this blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen.


Mutant cells beget cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendant of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of survival, selection, and colonization. It represents the first metastasis of a tumor that originated in the lung.


The man is occasionally short of breath. He feels a tingle of pain in the periphery of his lung. Occasionally, he senses something moving under his rib cage when he walks. Another year passes, and the sensations accelerate. The man visits a physician and a CT is performed, revealing a rindlike mass wrapped around a bronchus in the lung. A biopsy reveals lung cancer. A surgeon examines the man and the CT scan of the chest and deems the cancer inoperable. Three weeks after that visit , the man returns to the medical clinic complaining of pain in his ribs and his hips. A bone scan reveals metastasis to the pelvis and the ribs.


Intravenous chemotherapy is initiated. The cells in the lung tumor respond. The man soldiers through a punishing regimen of multiple cell-killing drugs. But during the treatment, one cell in the tumor acquires yet another mutation that makes it resistant to the drug used to treat the cancer. Seven months after his initial diagnosis, the tumor relapses all over the body-in the lungs, the bones, the liver. On the morning of October, 17, 2004, deeply narcotized on opiates in a hospital bed in Boston and surrounded by his wife and his children, the man dies of metastatic lung cancer, a silver of asbestos still lodged in the periphery of his lung, He is seventy-six years old.



It is still not certain whether screening decreases morbidity or mortality or whether any gains resulting from screening outweigh the decreases in quality of life from treatment of asymptomatic cancers, and serum PSA is not ideal as a screening test, most clinicians recommend annual screening.     Merck Manual 19th Ed


screeningが、罹患率、死亡率を下げるかどうかはわからない。screeningによる利益が、無症状の人たちを治療することによるquality of lifeの低下の合計を上回るかどうかもわからない。PSA はscreeningの検査として(感度、特異度ともに)理想的ともいえない。それでも、大抵の医師は毎年のscreeningを勧める。


 Screening trials in cancer are among the most slippery of all clinical trials  – notoriously difficult to run, and notoriously susceptible to errors. To understand why, consider the odyssey from the laboratory to the clinic of a screening test for cancer. Suppose a new test has been invented in the laboratory to detect an early, presymptomatic stage of a particular form of cancer, say, the level of a protein secreted by cancer cells into the serum. The first challenge for such a test is technical: its performance in the real world.

がんにおけるscreeningの臨床試験というものは、あらゆる臨床試験のなかで最も当てにならない。計画実行がとてつもなく難しい上に、間違いを犯す確率もとてつもなく大きいからである。このことを理解するために、がんの screening test が laboratory から clinic にたどり着くまでの波乱に満ちた道筋を見てみよう。がんから血清に分泌されるある蛋白の濃度のような無症状のある種の早期がんを見つける新しい test が laboratory で発見されたとしよう。このような test の最初の試練は、実際の診療における技術的な問題だ。

Epidemiologists think of screening tests as possessing two characteristic performance errors. The first error is overdiagnosis—when an individual tests positive in the test but does not have cancer. Such individuals are called “false positives.” Men and women who falsely test positive find themselves trapped in the punitive stigma of cancer. The familiar cycle of anxiety and terror (and the desire to “do something”) that precipitates further testing and invasive treatment.

疫学者は、screening tests には二つの実行上の欠点があるという。まず overdiagnosis (個々のtests が陽性で、がんを持たない場合、偽陽性)、偽陽性とされた人々は、がんという懲罰的な汚点にさらされたと感じる。お決まりの心配と恐怖の cycle(と何かをしなければという衝動)それが、更なる検査と侵襲性のある治療に駆り立てる。

The mirror image of overdiagnosis is underdiagnosis—an error in which a patient truly has cancer but does not test positive for it. Underdiagnosis falsely reassures patients of their freedom from disease. These men and women (“false negative” in the jargon of epidemiology) enter a different punitive cycle—of despair, shock, and betrayal—once their disease, undetected by the screening test, is eventually uncovered when it becomes symptomatic.

Overdiagnosis の正反対に位置するのが underdiagnosis だ。すなわち、がんでありながら、検査が陽性にならない場合。Underdiagnosis は、誤って、がんでないと保証してしまう。この“偽陰性”の人々は、別の懲罰的サイクルに入る。すなわちscreening test で見逃されたがんが(症状が出て)見つかった時に感じる、絶望、ショック、裏切り。

The trouble is that overdiagnosis and underdiagnosis are often intrinsically conjoined, locked perpetually on two ends of a seesaw. Screening tests that strive to limit overdiagnosis—by narrowing the criteria by which patients are classified as positive—often pay the price of increasing underdiagnosis because they miss patients that lie in the gray zone between positive and negative.

問題は overdiagnosis と underdiagnosis が、固く固定されたseesaw の両端のように、しばしば複雑に絡み合っているということなのだ。陽性と判定される範囲を狭めることにより overdiagnosis を少なくしようとすると、underdiagnosis が増えてしまう。陽性と陰性の狭間に存在するgray zone の患者を逃してしまうためだ。

An example helps to illustrate this trade off. Suppose-–to use Egan’s vivid metaphor—a spider is trying to invent a perfect web to capture flies out of the air. Increasing the density of that web, she finds , certainly increases the chances of catching real flies (true positives) but it also increases the chances of capturing junk and debris floating through the air (false positives). Making the web less dense, in contrast, decreases the chances of catching real prey, but every time something is captured, chances are higher that it is a fly.

このtrade offを説明するのに、Eganの生き生きとした例えを見てみよう。蜘蛛が、はえを捕まえる完璧な蜘蛛の巣を空中に張るとき、巣の密度を上げると、はえを捕まえるchances(真の陽性)は増える。だが、がらくたの破片を捕まえるchances(偽陽性)も増えてしまう。巣の密度を粗くすると、はえを捕まえるchances(真の陽性)は減るが、(偽陽性)も減る。

In cancer, where both overdiagnosis and underdiagnosis come at high costs, finding that exquisite balance is often impossible. We want every cancer test to operate with perfect specificity and sensitivity. But the technologies for screening are not perfect. Screening tests thus routinely fail because they cannot even cross this preliminary hurdle –the rate of over- or underdiagnosis is anacceptably high.

がんにおいては、overdiagnosisも underdiagnosisも高くつくので、両者の絶妙なバランスはほとんど不可能だ。我々は全てのがんのtestが感度、特異度ともに完璧であることを望む。しかしscreeningの技術は完璧ではない。大抵のScreening testsはoverdiagnosis、 underdiagnosisともにその頻度が高すぎて、とても受け入れることはできない。

Suppose, however, our new test does survive this crucial bottleneck. The rate of overdiagnosis and underdiagnosis are deemed acceptable , and we unveil the test on a population of eager volunteers, Suppose, moreover, that as the test enters the public domain, doctors immediately begin to detect early, benign- appearing, premalignant lesions—in stark contrast to the aggressive , fast-growing tumors seen before the test, Is the test to be judged a success?

しかしながら、あるnew testがこの窮地を潜り抜け、overdiagnosis、underdiagnosisともに許容範囲であり、実際に使われ始め、すぐに臨床の現場で早期の前がん状態が発見され始めたとしよう。このtestは成功とみなせるだろうか?

No; merely detecting a small tumor is not sufficient. Cancer demonstrates a spectrum of behavior. Some tumors are inherently benign, genetically determined t never reach the fully malignant state; and some tumors are intrinsically aggressive, and intervention at even an early , presymptomatic stage might make no difference to the prognosis of a patient. To address the inherent behavioral heterogeneity of cancer, the screening test must go further . It must increase survival.

否、小さなtumorを見つけるだけではだめなのだ。がんの動態は様々だ。あるtumorsは本来良性であり、遺伝子的に、完全な悪性状態には決してならない。あるtumorsは本質的に侵襲的であり、症状のない早期発見であっても予後に何の変化も起こさない。このがん固有の多様性に対応する為には、screening testの成功には、さらに、生存期間の増加が必要なのだ。

Imagine, now. That we have designed a trial to determine whether our screening test increases survival. Two identical twins, call them Hope and Prudence, live in neighboring houses and offered the trial. Hope chooses to be screened by the test. Prudence, suspicious of overdiagnosis and underdiagnosis, refuses to be screened.

screening testが生存期間を増すか否かを調べるtrialを想像してみよう。HopeとPrudenceという一卵性双生児が近所に住んでいて、あるtrialのofferを受けたとしよう。Hopeはそのofferを受け、Prudenceはoverdiagnosis、underdiagnosisへの懸念からそれを見送る。

Unbeknownst to Hope and Prudence, identical forms of cancer develop in both twins at the exact sametime—in 1990. Hope’s tumor is detected by the screening test in 1995, and she undergoes surgical treatment and chemotherapy. She survives five additional years, then relapses and dies ten years after her original diagnosis, in 2000. Prudence, in contrast, detects her tumor only when she feels a growing lump in her breast in 1999. She, too, has treatment, with some marginal benefit, then relapses and dies at the same moment as Hope in 2000.

HopeとPrudenceは与り知らず、全く瓜二つのがんが同時(1990)に両者に発生している。 Hopeのtumorは1995にscreening testにより発見され、手術、抗がん剤が行われる。それから5年後がんは再発し,がん発生から10年後(2000)彼女は死亡する。Prudenceは1999に胸のしこりに気付き、治療を受けるがほとんど恩恵はない。そして再発し、2000、Hopeと同時に死亡する。

At the joint funeral, as the mourners stream by the identical caskets, an argument breaks out among Hope’s and Prudence’s doctors. Hope’s physicians insist that she had a five-year survival; her tumor was detected in 1995 and she died in 2000. Prudence’s doctors insist that her survival was one year: Prudence’s tumor was detected in 1999 and she died in 2000. Yet both cannot be right: the twins died from the same tumor at the exact same time. The solution to this seeming paradox—called lead-time bias—is immediately obvious. Using survival as an end point for a screening test is flawed because early detection pushes the clock of diagnosis backward. Hope’s tumor and Prudence’s tumor possess exactly identical biological behavior. But since doctors detected Hope’s tumor earlier, it seems, falsely, that she lived longer and that the screening test was beneficial.

合同葬儀に於いて、参列者が同じ二つの棺の脇を流れるなか、Hopeと Prudenceの主治医が意見を交換する。Hopeの主治医は、彼女のtumorは1995に発見され、2000に死んだのだから、生存期間は5年だという。Prudenceの主治医は、Prudenceの生存期間は1年だという。両者とも正しいはずはない。双子は、同時に発生した全く同じtumorにより同時に死亡したのだ。この一見paradox(lead-time biasといわれる)の意味することは明らかだ。Survivalをscreening testの終点(有効性の指標)としてはいけない。なぜなら早期発見は、診断の時期を示す時計の針を押し戻してしまうからだ。HopeのtumorもPrudenceのtumorも全く等しい生物学的動態を示しているのに、Hopeのtumorは早く発見されたために、screening test のおかげでHopeはより長く生きたと誤認されてしまったのだ。

So our test must now cross an additional hurdle: it must improve mortality, not survival. The only appropriate way to judge whether Hope’s test was truly beneficial is to ask whether Hope lived longer regardless of the time of her diagnosis. Had Hope lived until 2010 (outliving Prudence by a decade), we could have legitimately ascribed a benefit to the test. Since both women died at the exact same moment, we now discover that screening produced no benefit.

それゆえ、screening testはさらなるhurdleを越えなければいけない。それは、生存期間ではなく、死亡率を改善しなければいけないのだ。Hopeのtestが真に有効であったか否かを判定する唯一適切な方法は、彼女のがんの診断時期とは無関係に、HopeがPrudenceより長く生きたかどうかを尋ねることだ。もしもHopeがPrudence より10年長く、2010まで生きたのならば、testの有効性は保証される。二人は同時に死んだのだから、screeningは無効だったのだ。

A screening test’s path to success is thus surprisingly long and narrow. It must avoid the pitfalls of overdiagnosis and underdiagnosis. It must steer past the narrow temptation to use early detection as an end in itself. Then it must navigate the treacherous straits of bias and selection. “Survival,” seductively simple, cannot be its end point. And adequate randomization at each step is critical. Only a test capable of meeting all these criteria—proving mortality benefit in a genuinely randomized setting with an acceptable over-and underdiagnosis rate—can be judged a success. With the odds stacked so steeply, few tests are powerful enough to withstand this level of scrutiny and truly provide benefit in   cancer.

screening testの成功への道は、かくも長くかつ狭い。それはoverdiagnosisとunderdiagnosisの落とし穴を避けなければいけない。それは早期発見を、screening testの終点として使いたい誘惑に負けてはいけない。それは油断のならないbiasとselectionの狭い道を通り抜けなければいけない。魅力ある“Survival,”を有効性の指標として使用してはいけない。screening testのすべてのstepにおけるrandomizationは絶対だ。真にrandomizationされた設定に於いて、容認できるover-and underdiagnosis rateを持って、死亡率の低下を証明できるtestのみが成功とみなせるのだ。そのoddsはかなり厳しく、がん診療に於いて、これらの要因の精査に十分に耐えて真に有効な利益をもたらすscreening testというものはほとんど存在しない。



But notably, at least at first glance, early detection had not translated into overwhelming numbers of lives saved.
But there was a pattern behind the deaths. When the groupes were analyzed by age, women above fifty-five years had benefited from screening, with a reduction in breast cancer deaths by 20 persent. In younger women, in contrast, screening with mammography showed do detectable benefit.   Malmo study 1988
The pooled analysis vindicated the Molmo results.  all the Swedish studies 2002


Mammography, in short, was not going to be the unequivocal ”savior” of all women with breast cancer. Its effects, as the statistician Donald Berry describes it, “are indisputable for a certain segment of women—but also indisputably modest in the segment” Berry wrote, “Screening is a lottery. Any winnings are shared by the minority of women. The overwhelming proportion of women experience no benefit and they pay with the time involved and the risks associated with screening. The risk of not having a mammogram until after age 50 is about the same as riding a bicycle for 15 hours without a helmet.” If all women across the nation chose to ride helmetless for fifteen hours straight, there would surely be several more deaths than if they had all worn helmets. But for an individual woman who rides her bicycle helmetless to the corner grocery store once a week, the risk is so minor that some would dismiss it outright.

要するに、Mammographyは乳がんを患うすべての女性にとっての決定的な救世主にはなりそうもなかった。その効果は統計学者のDonald Berryがいうように “ある部分の女性には明らかだ。しかし、同時にその効果がきわめてささやかであることも明らかだ。” Berryはいう。“Screeningは宝くじだ。当たるのは極一部の女性。圧倒的な数の他の女性には何の利益もなく、時間を無駄にして、screeningに付き物のriskを背負い込む。50才までmammogramをしないriskはhelmet無しで15分間 自転車に乗るriskに等しい。” 国中の全ての女性がhelmetなしで15分間自転車に乗るとすれば、全てがhelmetを着用する場合と較べ何人か死亡が増えるかもしれない。しかし、角の雑貨屋まで週に一度helmetなしで自転車に乗る女性にとってはそのriskは余りにも小さく、人によっては全く気にも掛けない。



Finally, it’s not enough to know what the chances are that you’ll be helped by early detection. You also need to know what the chances are that you won’t be helped, that you’ll be worried needlessly, that you’ll be overdiagnosed and treated for no reason, or that you’ll be hurt by treatment. A good randomized trial can provide all the information required to get the big picture (although it may not be easy to find all the information in one report).

最後に、早期発見によりどのような益の可能性があるかを知るだけでは十分ではない。不必要に不安にさせられたり、overdiagnosis(過剰診断)により意味も無く治療されたり、それにより不利益を被ったり、といった負の面の可能性も知らなくてはいけない。信頼に足るrandomized trialは全体像を知るに必要な知識を与えてくれる。(一つの報告ですべての情報を得ることは難しいかもしれないが。)

To show you what I mean, let me return to best-studied screening test: screening mammography. Worldwide, over a half a million women have been studied in ten randomized trials. The trials’ finding aren’t all the same, but the consensus is that mammography does help. Combining data from all the trials, the best estimate is that mammography reduces the death rate from breast cancer by about 20 percent. That’s a statement of relative risk. Here are the current absolute risks of breast cancer death for the typical fifty-year-old woman over the course of ten years: from about 5 per 1,000 without mammography to 4 per 1,000 with mammography. That means about 1,000 women have to be screened for ten years for one to benefit.

私のいいたいことを示すために、screening mammographyについてよく調べられたscreening testに戻ろう。50万を超える女性が、世界中の10のrandomized trialsで調べられている。Trialの結果は様々だが、mammographyに益がある点においては意見が一致している。すべてのtrialsからの最良の結果によるとmammographyは死亡率を約20%減少させる。これは相対riskだ。現在の典型的50才女性の60才になるまで10年間の乳がん死の絶対riskは、mammographyをやらない 1,000人中5人から、 mammographyをやる 1,000人中4人に減少する。これは、1人の益のため1,000人が10年間 mammographyを必要とすることを意味する。

While it’s easy to focus on the one woman who benefits, what about the other 999? They get screened but do not benefit. For each woman who benefits, at least two are overdiagnosed and treated needlessly. Some have estimated the number to be as high as ten. Furthermore some women, about 5 to 15 per 1,000, will have their cancer detected at a younger age with mammography, yet their prognosis will remain unchanged (those destined to die still will, those destined to survive would have done just as well if diagnosed later)—so they just live longer knowing they have cancer. And many women. 250 to 500 per 1,000, will experience a false alarm—a mammogram that indicates cancer might be present but that is ultimately proved wrong (by a second mammogram or a biopsy). This number is particularly high in the United States, where researchers have estimated that over a ten-year period, half the women who get annual mammography have at least one false alarm, and about a fifth of them have at least one biopsy.”

益を得る1人の女性に焦点を当てることはたやすいが、他の999人はどうだろう? 彼女らはscreeningを受けても益はない。益を得る1人当たり、少なくとも2人は過剰診断され、不必要な治療を受ける。過剰診断は最大10人の可能性があるという。さらに1,000人あたり5から15人はmammographyにより、より早くがんが発見されるが予後は変わらないという。(死ぬべきものは死ぬべき時に死に、生きるべきものは診断時期が遅れても生きるだけ生きる)彼女らはがんを意識してより長く生きることになる。そして多くの女性(1000人当たり250人から500人)が間違ったalarmを受け取る。Mammogramによりがんがあるかもしれないとされ、結局は、再度のmammogramかbiopsyにより間違いとわかる例。この数はUnited Statesでは特に多い。10年間、毎年mammogramを受ける女性の半分は少なくとも1回のalarmを受け取り、その内の1/5は少なくとも1回のbiopsyを受けるという。

I think table 10.2 serves as a template for the kind of balanced information people need to make truly informed choices about whether or not to be screened.   H.GILBERT WELCH



Why did a simple, reproductive, inexpensive, easily learned technique—an X-ray image to detect the shadow of a small tumor in the breast—have to struggle for five decades and through nine trials before any benefit could be ascribed to it?


Part of the answer lies in the complexity of running early–detection trials, which are inherently slippery, contentious, and prone to error. Edinburgh was undone by flawed randomization; the BCDDP by non-randomization. Shapiro’s trial was foiled by a faulty desire to be dispassionate; the Canadian trial by a flawed impulse to be compassionate.

答えの一つは早期発見trialsを行うに当たってのその複雑性にある。それはもともと意味のある計画が立てづらく、色々な考え方があって、誤りを犯しやすいものなのだ。Edinburghにはrandomizationに問題があったし、BCDDPにはそもそもrandomizationがなかった。Shapiro’s trialは誤った公平無私を目指してうまくいかなかったし、Canadian trialは同情に左右されて失敗した。

Part of the answer lies also in the old conundrum of over- and under-diagnosis—although with an important twist. A mammogram, it turns out , is not a particularly good tool for detecting early breast cancer. Its false-positive and false-negative rates make it far from an ideal screening test. But the fatal flaw in mammography lies in that these rate are not absolute: they depend on age. For women above fifty-five, the incidence of breast cancer is high enough that even a relatively poor screening tool can detect an early tumor and provide a survival benefit. For women between forty and fifty years, though, the incidence of breast cancer sinks to a point that a “mass” detected on a mammogram, more often than not, turns out to be a false positive. To use a visual analogy: a magnifying lens designed to make small script legible does perfectly well when the font size is ten or even six points. But then it hits a limit. At a certain size font, chances of reading a letter correctly become about the same as reading a letter incorrectly. In women above fifty-five, where the “font size” of breast cancer incidence is large enough, a mammogram performs adequately, But in women between forty and fifty, the mammogram begins to squint at an uncomfortable threshold—exceeding its inherent capacity to become a discriminating test. No matter how intensively we test mammography in this group of women, it will always be a poor screening tool.

答えの一つはまた古くからの難題であるover- and under-diagnosisにある。重要なひねりが加わっているが。Mammogramは早期乳がんを見つける道具としては取り立てて優れてはいない。その偽陽性率、偽陰性率をみれば、とても理想的なscreening testとは言えない。だがMammogramの致命的な欠陥は、それらの率が絶対ではないということなのだ。それらは年齢に依存するのだ。55才以上の女性に対しては、罹患率が高いので、比較的劣悪な道具でも、早期がんを何らかの利益のある形で見つけることができる。だが、40才から50才の女性に対しては、罹患率が低い為、mammogramで見つけられた腫瘤は非常にしばしば偽陽性となってしまうのだ。わかりやすい例えを使えば、小さな活字を読みやすくする拡大レンズは、活字のfont sizeが10から6までが限界だ。それ以下になってあるfont sizeになると、正しく識別される割合は、正しく識別されない割合と同じになってしまう。55才以上で、乳がん罹患率のfont sizeが十分大きい場合は、mammogramは適切といえる。しかしながら40才から50才の女性では、mammogramではよく見えなくなってきて、適切なtestとは言えなくなってくる。このgroupでは、mammogramはいくら慎重に行っても劣悪な道具であることに変わりはないのだ。

But the last part of the answer lies, surely, in how we imagine cancer and screening. We are a visual species. Seeing is believing, and to see cancer in its early, incipient form, we believe, must be the best way to prevent it. As the writer Malcom Gladwell once described it, “This is a textbook example of how the battle against cancer is supposed to work. Use a powerful camera. Take a detailed picture, Spot the tumor as early as possible. Treat it immediately and aggressively…. The danger posed by a tumor is represented visually. Large is bad; small is better.”

だが最後の答えは、もちろん我々ががんとscreeningをどう捉えているかにある。我々は視覚に頼るところが大きい。見るは信じること。がんを極早期に視覚で捉える事ががんの予防に最善であると信じて疑わない。Malcom Gladwellが、かって述べたように “これはいかにしてがんと闘うべきかの教科書的な例だ。強力なcamera.を使うべきだ。詳細な画像をとり、可能な限り早期に腫瘤を指摘すべきだ。すぐに、そして強力に治療を始めるべきだ。腫瘤の危険度は見ればわかる。大きければ悪く、小さければ小さいほど良い。”

But powerful as the camera might be , cancer confounds this simple rule. Since metastasis is what kills patients with breast cancer, it is, of course, generally true that the ability to detect and remove pre-metastatic tumors save women’s lives. But it is also true that just because a tumor is small does not mean that it is pre-metastatic. Even relatively small tumors barely detectable by mammography can carry genetic programs that make them vastly more likely to metastasize early. Conversely large tumors may inherently be genetically benign-unlikely to invade and metastasize. Size matters, in other words-but only to a point. The difference in the behavior of tumors is not just a consequence of quantitative growth, but of qualitative growth. A static picture cannot capture this qualitative growth. Seeing a small tumor and extracting it from the body does not guarantee our freedom from cancer- a fact that we still struggle to believe.


In the end, a mammogram or a Pap smear is a portrait of cancer in its infancy. Like any portrait, it is drawn in the hopes that it might capture something essential about the subject—its psyche, its inner being, its future, its behavior. “All photographs are accurate,” the artist Richard Avedon liked to say, “but none of them is the truth.” But if the “truth” of every cancer is imprinted in its behavior, then how might one capture this mysterious quality? How could scientists make that crucial transition between simply visualizing cancer and knowing its malignant potential, its vulnerabilities, its patterns of spread—its future?

つまる所、 mammogram、Pap smearは、がんの幼少期のportraitにすぎない。どの場合でも、portraitは対象の本質的な何かを求めて描かれる。(その心、内に秘めたもの、未来、ふるまい) Richard Avedonは好んでいった。“全ての写真は正確だ。だがそのどれも真実ではない。”  だがすべてのがんの真実がその動きの中に刻まれているとしたら、この神秘的な本質をどのようにして捉えたらよいのだろう。科学者は、どうしたら、単にがんを見るだけから、がんの悪性度の程度、弱点、転移のpattern、そしてその未来を知ることができるようになるのだろう。



Forkman’s Harvard colleague Stan Korsmeyer found other activated pathways in cancer cells, originating in mutated genes, that also blocked cell death, thus imbuing cancer cells with the capacity to resist death signals. Other pathways allowed cancer cells to acquire motility, the capacity to move from one tissue to another—initiating metastasis. Yet other gene cascades increased cell survival in hostile enviroments, such that cancer cells traveling through the bloodstream could invade other organs and not be rejected or destroyed in environments not designed for their survival.

ForkmanのHarvard での同僚であるStan Korsmeyerは、がん細胞にdeath signalに抗して細胞死を防ぐ能力を与える、変異遺伝子に始まる活性化されたpathwayを発見した。 別のpathwayは一つの組織から他の組織に移動する能力(転移する能力)をがん細胞に与えた。他のgene cascadeは、血流中のがん細胞が排除されずに他の臓器を侵略できるように、生存に適さない環境で生き延びる能力をがん細胞に与えた。

Cancer, in short, was not merely genetic in its origin; it was genetic in its entirely. Abnormal genes governed all aspect of cancer’s behavior. Cascades of aberrant signals, originating in mutant genes, fanned out within the cancer cell, promoting survival, accelerating growth, enabling mobility, recruiting blood vessels, enhancing nourishment, drawing oxygen—sustaining cancer’s life.

がんは、その起源のみが遺伝的なのではない。そのすべてにおいて遺伝的なのだ。変異遺伝子は、がんのすべての動きを支配する。変異遺伝子に発するaberrant signals のcascadesは、がん細胞内の、寿命を延ばし、成長を促し、動きを増やし、血管を増殖させ、栄養豊かにし、酸素を誘導し、がん細胞の命を支えるのだ。

These gene cascades, notably, were perversions of signaling pathways used by the body under normal circumstances. the motility genes activated by cancer cells, for instance, are the very genes that normal cells use when they require movement through the body. Such as when immunological cells need to move toward sites of infection. Tumor angiogenesis exploits the same pathways that are used when blood vessels are created to heal wounds.

これらのgene cascadesは、正常時に使用されるsignaling pathwaysの悪用である。例えば、がん細胞によって活性化されるmotility genes は、動きを必要とする時に正常細胞が使用する遺伝子そのものなのだ。(例えば、免疫細胞が感染部位に移動する時に必要とするように) 腫瘍の血管造成は、創傷治癒のため形成される血管を作るpathwaysと同じものを流用しているのだ。

Nothing is invented; nothing is extraneous. Cancer’s life is a recapturation of the body’s life, its existence a pathological mirror of our own. Susan Soutag warned against overburdening an illness with metaphors. But this is not a metaphor. Down to their innate molecular core, cancer cells are hyperactive, survival-endowed, scrappy, fucund, inventive copies of ourselves.


The “mountains” in the cancer genome—i.e., genes most frequently mutated in a particular form of cancer—have another property. They can be organized into key cancer pathways. In a recent series of studies, Vogelstein’s team at Hopkins reanalyzed the mutations present in the cancer genome using yet another strategy. Rather than focusing on individual genes mutated in cancers, they enumerated the number of pathways mutated in cancer cells. Each time a gene was mutated in any component of the Ras-Mek-Erk pahway, it was classified as a “Ras pathway” mutation. Similarly, if a cell carried a mutation in any component of the Rb signaling pathway, it was classified as “Rb pathway mutant,” and so forth, until all driver mutations has been organized into pathways.

(ある種のがんにおける最も変異を起こす遺伝子群である)遺伝子の山は、もう1つの特性を持つ。それらは、keyとなるcancer pathwaysを形成するのだ。最近、HopkinsのVogelstein’s teamは、がんの遺伝子変異を通常とは異なる方法で解析した。がんにおける個々の変異遺伝子に注目するのではなく、がんに於いて変異したpathwaysを数え上げたのだ。Ras-Mek-Erk pahwayの構成遺伝子に変異があった場合は、Ras pathwayと分類される。同様に、Rb signaling pathwayのどの構成遺伝子に変異があっても、それは、Rb pathway 変異と分類される。すべての主要な遺伝子変異がpathwaysに分類されるまで、彼らはこれを続けたのだ。

How many pathways are typically dysregulated in a cancer cells? Typically, Vogelstein found, between eleven and fifteen, with an average of thirteen. The mutational complexity on a gene-by-gene level was still enormous. Any one tumor bore scores of mutations pockmarked throughout the genome. But the same core pathways were characteristically dysregulated in any tumor type, even if the specific genes responsible for each broken pathway differed from one tumor to the next. Ras may be activated in one sample of bladder cancer, Mek in another; Erk in the third—but in each case, some vital piece of the Ras-Mek-Erk cascade was dysregulated.

がん細胞に於いては、通常いくつのpathwayに異常が見られるのだろう。Vogelsteinは11から15、平均13だといっている。遺伝子毎の変異の複雑さは極めて大きく、ある腫瘍は遺伝子全体に沢山の変異を抱える。しかし、異常をきたしたpathwayに大きく関係する遺伝子が腫瘍毎に異なっても、腫瘍のtypeに共通するpathwayに異常が見られるのだ。Rasがある膀胱がんで活性化されているとする。Mekが別の膀胱がんで、Erkがさらに別の膀胱がんで活性化されているとしても、全てのがんにおいて、要となるRas-Mek-Erk cascadeに異常が見られるのだ。

The bedlam of the cancer genome, in short, is deceptive. If one listens closely, there are organizational principles. The language of cancer is grammatical, methodical, and even—I hesitate to write—quite beautiful. Genes talk to genes and pathways to pathways in perfect pitch, producing a familiar yet foreign music that rolls faster and faster into a lethal rhythm. Underneath what might seem like overwhelming diversity is a deep genetic unity. Cancers that look vastly unlike each other superficially often have the same or similar pathways unhinged. “Cancer “ as one scientist recently put it, “really is a pathway disease”.

がん遺伝子の狂ったような混乱は見せかけにすぎない。耳を澄ませば、整然とした法則が聞いて取れる。がんの言語は文法的で、規則正しく、書くのもはばかれるが極めて美しい。遺伝子は遺伝子に、 pathwayはpathwayに完璧なpitch(音高)で話しかける。結果、死のrhythmに転げるように突き進む、通俗だが異質の音楽が生まれるのだ。圧倒的な多様性と思われる背後には、遺伝子の深い統合がある。表面的には、お互いに全く異なるように見えるがん同士にあっても、同じ、またはよく似たpathwayが活性化されているのだ。ある科学者がいったように、がんとは、pathwayの病気なのだ。

Indeed, cancer stem cells have acquired the behavior of normal stem cells by activating the same genes and pathways that make normal stem cells immortal—except, unlike normal stem cells, they cannot be lulled back into physiological sleep. Cancer, then, is quite literally trying to emulate a regenerating organ—or perhaps, more disturbingly, the regenerating organism. Its quest for immortality mirrors our own quest, a quest buried in our embryos and in the renewal of our organs. Someday, if a cancer succeeds, it will produce a far more perfect being than its host—imbued with both immortality and the drive to proliferate. One might argue that the leukemia cells growing in my laboratory derived from the woman who died three decades earlier have already achieved this form of perfection.

勿論、がん幹細胞は、正常幹細胞を不死にするgenes and pathwaysを活性化させることにより、正常肝細胞の挙動を獲得した。もっとも生理的休眠に入ることはないが。そして、がんは文字通り臓器を再生する。にわかには信じがたいことだが、多分、生体をも再生させようとしているのだ。がんの不死への希求は、胚、臓器再生に潜む我々自身の希求と同じものだ。いつか、がんは、不死と増殖を完璧にして、hostよりはるかに完全な存在になっているかもしれない。私の研究室にある、30年前に死んだ女性からの白血病細胞は、すでにこのような完全な存在だという人もいる。

Taken to its logical extreme, the cancer cell’s capacity to consistently imitate, corrupt, and pervent normal physiology thus raises the omnious question of what normalcy is. Cancer, Carla said, is my new normal, and quite possibly cancer is our normalcy as well, that we are inherently destined to slouch toward a malignnt end. Indeed, as the fraction of those affected by cancer creeps inexorably in some nations from one in four to one in three to one in two, cancer will, indeed, be the new normal—an inevitability. The question then will not be if we will encounter this immortal illness in our lives, but when.

論理的に突き詰めれば、正常の生理機能を絶えず模倣、悪用、濫用するがん細胞は、何が正常なのかという不吉な疑問を提起する。 Carla は、がんは私の新しい正常なの、といったが、がんは我々にとっても正常なのかもしれない。我々は、(紆余曲折はあるにせよ)、本質的に、悪性の終局へ向かって進むように運命づけられている存在なのかもしれない。がんに罹るのが、4人に1人から、3人に1人、2人に1人と急増する国に於いては、がんは避ける事ができない新しい正常になるだろう。その場合、問題は、もしがんになったらではなく、なった時には、になるのだ。

The answers to these questions are embedded in the biology of this incredible disease. Cancer, we have discovered, is stitched into our genome. Oncogenes arise from mutations in essential genes that regulate the growth of cells. Mutations accumulate in these genes when DNA is damaged by cartinogens, but also by seemingly random errors in copying genes when cells divide. The former might be preventable, but the latter is endogenous. Cancer is a flaw in our growth, but this flaw is deeply entrenched in ourselves. We can rid ourselves of cancer, then, only as much as we can rid ourselves of the processes in our physiology that depend on growth—aging, regeneration, healing, reproduction.

これらの問いに対する答えは、この途方もない病気の生物学に埋もれている。がんは我々のgenomeに縫い付けられているのだ。がん遺伝子は、細胞の成長をつかさどる主要な遺伝子の変異から発生する。DNAがcartinogenによって傷つくと変異は遺伝子に蓄積する。しかし細胞分裂時のコピーミスによっても発生する。前者は予防可能だが、後者は内因性なので如何ともしがたい。がんは我々の成長に於ける傷だが、我々自身に深く食い込んでいる。がんは、aging, regeneration, healing, reproductionを司る生理学の過程で無くても差し支えないものしか取り除くことができない。

Science embodies the human desire to understand nature; technology couples that desire with the ambition to control nature. These are related impulses—one might seek to understand nature in order to control it—but the drive to intervene is unique to technology. Medicine, then, is fundamentally a technological art; at its core lies a desire to improve human lives by intervening on life itself. Conceptually, the battle against cancer pushes the idea of technology to its far edge, for the object being intervened upon is our genome. It is unclear whether an intervention that discriminates between malignant and normal growth is even possible. Perhaps cancer, the scrappy, fecund, invasive, adaptable twin to our own scrappy, fecund, invasive, adaptable cells and genes, is impossible to disconnect from our bodies. Perhaps cancer defines the inherent outer limit of our survival. As our cells divide and our bodies age, and as mutations accumulate inexorably upon mutations, cancer might well be the final terminus in our development as organisms.

Scienceは自然を理解したいと思う我々の願望を形にする。これと相俟って自然を左右したいとするのがTechnologyだ。これらは切っても切れない衝動だ。人は自然をcontrolするために自然を理解しようとする。しかし自然に介在しようとする力はtechnologyにある。Medicineは基本的にはtechnological artだ。その神髄はlifeそのものに介在することによりhuman liveを改善しようとする。概念上は、がんとの闘いはidea of technologyを最先端まで推し進めたものだ。なぜなら、介在されるものは我々のgenomeだからだ。悪性と正常を区別する介在が可能かどうかも分からない。多分、細胞、遺伝子ともに、支離滅裂で多産で侵略的で適応能力が高い正常のものと瓜二つのがんは、我々の体から切り離すことはできないのかもしれない。がんは我々の生存の限界を規定しているのだろう。時間とともに、細胞が分裂を重ね、突然変異を容赦なく積み重ねて発生するがんは、我々の生物としての進化の帰結すなわち最終到着点なのかもしれない。


Give Atossa metastatic pancreatic cancer in 500 BC and her prognosis is unlikely to change by more than a few months over twenty-five hundred years. If Atossa develops gallbladder cancer that is not amenable to surgery, her survival changes only marginally over centuries. Even breast cancer shows a marked heterogeneity in outcome. If Atossa’s tumor has metastasized, or is estrogen-receptor negative, Her-2 negative, and unresponsive to standard chemotherapy, then her chances of survival will have barely changed since the time of Hunter’s clinic. Give Atossa CML or Hodgkin’s disease, in contrast, and her life span may have increased by thirty or forty years.

500BCにおける転移をともなった膵臓がんの予後は、2500年を経た現在と数か月程度しか違わない。手術適応のない胆嚢がんの予後は、数世紀を経ても変わらない。乳がんでさえ、驚くべき多様性を示す。Atossaの乳がんが、転移を伴い、estrogen受容体陰性(tamoxifen無効)、Her-2陰性(Herceptin無効)であり、通常の抗がん剤に反応しなければ、彼女の生命予後は、Hunter’s clinic の時代(18世紀)とさほど変わらない。翻って、AtossaのがんがCML、または Hodgkin’s diseaseであったとすれば、彼女の余命は、30年から40年伸びているかもしれないのだ。

Part of the unpredictability about the trajectory of cancer in the future is that we do not know the biological basis for this heterogeneity. We cannot yet fathom, for instance, what makes pancreatic cancer or gallbladder cancer so markedly different from CML or Atossa’s breast cancer. What is certain, however, is that even the knowledge of cancer’s biology is unlikely to eradicate cancer fully from our lives. As Doll suggests, and as Atossa epitomizes, we might as well focus on prolonging life rather than eliminating death. This War on Cancer may best be “won” by redefining victory.



And there is a subtler reason to remember this story: while the content of medicine is constantly changing, its form, I suspect remains astonishingly the same. History repeats, but science reverberates. The tools that we will use to battle cancer in the future will doubtless alter so dramatically in fifty years that the geography of cancer prevention and therapy might be unrecognizable. Future physicians may laugh at our mixing of primitive cocktails of poisons to kill the most elemental and magisterial disease known to our species. But much about this battle will remain the same:  the relentlessness, the inventiveness, the resilience, the queasy pivoting between defeatism and hope, the hypnotic drive for universal solutions, the disappointment of defeat, the arrogance and the hubris.

この話を持ち出したのには、ちょっとしたわけがある。医学の中味は常に変わるが、その形は驚くほど変わらない。歴史は繰り返すが、科学は響き渡る。がんに用いる道具は50年もたつと驚くほど変化して、がんの予防や治療の様子は思いもよらないものになっているかもしれない。その時の医者は、我々が人類に知られた最も基本的でそして厳しい疾患であるがんに使用した原始的な毒のcocktail を笑うかもしれない。しかしながら、その時であっても、がんとの闘いのほとんどは、今とほとんど変わっていないはずだ。執拗な努力、工夫、立ち直り、敗北と希望の間の居心地の悪さ、根本的な解決法を求める飽くなき執念、敗北による失望、傲慢とうぬぼれも。


The EMPEROR of All MALADIES            A Biography of Cancer

SIDDHARTHA MUKHERJEE  is a cancer physician and researcher. He is an assistant professor of medicine at Columbia University and a staff physician at Columbia University Medical Center. A former Rhodes Scholar.                 WINNER of the PULITZER PRIZE         2010



 If you are a nonsmoking woman, breast cancer is the cancer to be most concerned about. A new breast lump should be investigated with a diagnostic mammogram. Most women with breast cancer will do well (as, thankfully, my wife did). Yet some will die. Given this fact, it is certainly reasonable to consider screening as a way to reduce the risk of breast cancer death. But screening increases another risk—the risk of overdiagnosis.


It has been difficult to have a rational discourse about screening mammography. Many in the cancer community fear that the public can’t deal with the reality that screening helps some and hurts others. They worry about sending any messages that might discourage people from getting screened.

今までにScreening mammography に関して理性的に意見を交わすことは困難であった。cancer communityの多くの人達は、(screeningはある人を助け、ある人を傷つける)という現実を、一般市民は、受け入れることができないのではと恐れる。彼らは、一般市民がScreeningを避けるようになるかもしれないmessageを出すことには消極的だ。

This may explain why none of the government-run mammography screening programs in seven European countries mentions overdiagnosis in the patient-information pamphlets. But by hiding overdiagnosis, they exacerbate the problem. If the public doesn’t know about the problem of overdiagnosis, then all the forces line up to make the problem worse. Radiologists will look harder at images, pathologists will look harder at biopsy specimens—both afraid only of missing cancer, not of overdiagnosis. Medical journals will reflexively conclude that best test is always the one that sees more, not less. So will the news media.

Europeの7か国における、政府主導のmammography screening programが、一般市民むけpamphletのなかで、過剰診断について言及していないのは、これが理由だろう。だが過剰診断を隠せば問題はこじれる。市民が過剰診断を知らなければ、事はすべての面で面倒になる。Radiologistは画像をより細かく読もうとする。病理は生検標本をより細かく判断しようとする。過剰診断ではなく、見逃しを恐れて。Medical journalはより多くがんを見つけるtestがbestであると反射的に結論付け、news mediaもそれに追従する。

Of course, these concerns also apply to screening for other cancers. Encouragingly, the prostate cancer experience does seem to be changing the cancer community. There is probably no organization that has pushed more for screening in the past than the American Cancer Society. But their current chief medical officer frequently expresses his concern about the inevitable problem of overdiagnosis with cancer screening to physicians and the public alike. The Centers for Disease Control now acknowledges overdiagnosis in their decision guide for prostate cancer screening. And the National Cancer Institute’s PDQ (Physician Data Query) informs health professionals and patients about the problem of overdiagnosis in screening for a number of cancers. I’m cautiously optimistic that a more balanced discussion about mammography is coming.

勿論、これらの懸念は、他のがんにおけるscreeningについてもあてはまる。勇気づけられることに、前立腺がんにおける経験がcancer communityを変えつつあるように思われる。多分、American Cancer Societyほど強力にscreeningを推進した団体は過去に存在しないが、現在のchief medical officerは、医師や市民向けに(同じように)cancer screeningに付き物の過剰診断の問題についてしばしば懸念を表明している。The Centers for Disease Controlは前立腺がんのscreeningの事前説明に過剰診断についてはっきり書いてある。the National Cancer Institute’s PDQ (Physician Data Query)は、いくつかのがんについて、医師、市民向けに、過剰診断の問題についてきちんと知らせている。私は、手放しではないが、mammographyにおいて、よりbalanceのとれた議論が出来るようになるのはほとんど間違いないと楽観的だ。

Assuming this assessment is correct, I wonder if we might be ready for one more randomized trial. I believe we could reduce the problem of overdiagnosis (as well as reduce false alarms) yet still preserve the death benefit if we were willing to look less hard for breast cancer. The second Canadian trial tells us that screening mammography has no apparent benefit over a carefully standardized physical examination of the breast. But the practical reality is that it is much easier to standardize the practice of the relatively few mammographers in the United States than it is to standardize the practice of the very large number of primary care practitioners who might perform the careful physical examinations (not to mention dealing with the problem of finding the time for them to do so) So I’d like to see a trial comparing current mammography practice with a more conservative one: calling a mammogram suspicious for cancer (and undertaking a biopsy) only if the detected abnormality could plausibly be felt (a size, say, greater than one centimeter).

この予想が正しいとすれば、もう一つのrandomized trialの準備をしておいた方が良いかもしれない。私は、より細かく乳がんを見つけようとしなければ、death benefitを損なうことなく、過剰診断の問題(false alarmsも)を減らすことができると信じている。二番目のCanadian trialによれば、注意深く標準化された診察はmammographyに遜色ないとされている。(現実には、より少ないmammographers のやり方を標準化するほうが、多くの時間を取って、多数の家庭医の触診のやり方を標準化するより実際的であると思われる) であるから、触診において、疑わしい場合(そう、1cmより大きい腫瘤がふれた時)のみmammogram、biopsyの出番を与えるという保守的なやり方を、現行のmammography のやり方と比較するtrialの結果を見てみたいと思うのだ。

Cancer screening—the purposeful effort to search for early cancers in those who are well—has led to a lot of over-diagnosis. But sometimes we stumble onto a cancer when we’re not even looking for it.  

目的を持ったcancer screening はしばしば過剰診断をもたらすが、時には、探してもいないcancerを、たまたま見つけてしまうこともある。    H.GILBERT WELCH

DR.H.GILBERT WELCH is a professor at the Dartmouth Institute for Health Policy and Clinical Practice.



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