未来癌症能够被治愈吗？对这个问题的回答，取决于我们如何定义“治愈”。治愈是否意味着彻底消灭病人肿瘤中的所有癌细胞及其后代细胞？还是说，只要能够控制肿瘤不生长、不转移、不威胁患者的生命，就意味着癌症已经被治愈了？
我们已经看到，癌症是人体细胞之间所发生的演化的结果。演化告诉我们，失控正是癌症的本性之一。这就是癌症的本质：不遵循多细胞合作的正常规则、不受控制的细胞行为。癌症是我们体内细胞层面演化的结果，这样的演化有利于不守本分的细胞。在正常情况下，我们的身体一直在监测并抑制在多细胞合作中作弊的细胞。但是，在癌症中，特别是在晚期癌症中，细胞层面的演化完全处于失控状态。
我们也知道，癌症会继续演化，甚至在我们治疗它的时候尤为如此。因此，对于晚期癌症，要通过彻底清除癌细胞来治愈是极其困难的，因为不管我们用什么治疗方法，癌症仍会随之演化。不过，还有另一种可能性——我们可以尝试通过控制癌症来达到治愈癌症的目的。正是因为癌症可以随着我们的治疗而演化，我们才有希望通过控制而治愈癌症。
癌症在不断演化，但我们有能力预测其演化，并从战略上来规划我们的应对措施。我们可以诱骗它，让它走进死胡同，因其弱点而送命，并把癌症变成我们能够与之共存的东西。如果我们能够调整治疗方法，让癌症的演化选择攻击性较低的癌细胞，支持正常细胞，防止肿瘤变得太大——就像适应性治疗一样，我们也许就能够控制住癌症，把它牢牢攥在手心里。
对于用传统的治疗方法不大可能治愈（即癌症得到完全缓解且复发率极低）的癌症，我们的目标应该是控制住它。如果我们在思考癌症治疗时继续秉持传统的你死我活的战争观念，那么停止治疗看起来就像是“放弃抵抗”或“输掉战斗”。已故的演化生物学家史蒂芬·杰伊·古尔德（Stephen Jay Gould）在一篇关于他个人与癌症抗争的文章中说：“我更倾向于那种更军事化的观点，把死亡当成我们的终极敌人——而且，对于面对死亡大发雷霆的人，我没有什么可责备的。”[34]然而，战争结果并不一定只关乎你的武器装备和攻击性，你也可以预测敌人的下一步行动，在谋略上碾压他们。
接受癌症是我们的一部分，并把它作为一个不可捉摸、不断适应的对手，做好与其进行长期的战略互动的准备——如果能够做到这些，我们会获益良多。面对事实，接受一个与癌症共存的不确定的未来，而不是死抱着虚假的希望，以为有一天我们会找到一种神奇的武器，把癌症从这个世界上消灭殆尽——要做到这些，需要很大的勇气。
癌症领域的许多研究人员正在努力确定一些关键参数（例如演化–生态指数），我们在运用诸如适应性疗法等方法来进行治疗、制定战略决策时，会用到这些参数。[35]确定这些参数，可以帮助我们做出明智的决定，确定什么时候应该进行积极的治疗和根除，什么时候应该进行管控和遏制。这种思维转变，把癌症看作一种慢性、可控的疾病，为癌症的治疗和预防拓展了新的道路。[36]
那么，当我们的身体控制不住癌症时，我们该怎么办呢？归根结底，这个问题的正确答案将取决于患者所患癌症的类型、进展阶段，以及患者想要怎样度过之后的人生。如果患者的癌症治愈的可能性很高，和/或尚处于癌症早期，那么采取以治愈为目标的积极治疗方法，很可能就是正确的选择。
这让我们回想起我在本书开始所提到的雅典娜和阿瑞斯所采取的不同策略。雅典娜是智慧和战争的女神。阿瑞斯只是战争之神，活着就是为自己而侵略，在战乱中崛起。而另一方面，雅典娜运用她的智慧和战略推理来控制她的敌人，同时又能够避免代价高昂的战斗。我们要控制敌人，而不是带来死亡和破坏，造成巨大的损失。标准的高剂量化疗就是阿瑞斯的战争风格，而适应性疗法和我们在本章中谈到的一些其他策略则是雅典娜的战争风格。
癌症会影响到我们每一个人，它是全球第二大死因。它影响了我们的家庭、我们的社区、我们的世界和我们的世界观。它的势力范围远不止于此：它超越了现代人类，可以一直追溯到多细胞生命的起源和整个生命之树。从更广泛的演化视角看待癌症，我们就会看到，在与癌症的斗争中我们并不孤单——从多细胞生命出现伊始，生命就一直在与癌症斗争。我们看到，演化既是我们患上癌症的原因，同时也给予了我们控制癌症的希望。
如果能够理解并认识到我们与癌症的演化历史，我们就能够为人类健康和福祉塑造一个更美好的未来。自多细胞生命出现伊始，癌症就一直是生命的一部分，每一步的演化都与我们的演化相伴而行。从一开始，我们就和这个吃白食占便宜的室友住在了一起。不过，尽管有这么一个不受欢迎的伙伴，我们的演化依然取得了成功。
演化的力量是强大的，它塑造了我们这个星球上的生命多样性，也塑造了我们体内癌细胞的多样性和韧性。我们减轻癌症负担最有希望的途径，就是将这种力量掌握在自己手中——沿着某种轨迹来塑造肿瘤的演化，防止肿瘤细胞演化成我们无法控制的东西，将我们杀死。一方面，癌症演化是我们身体中所发生的失控的演化，而另一方面，或许我们还未意识到，我们也许能够控制癌症演化轨迹——通过测量肿瘤的动态变化，制定治疗方案，将肿瘤演化引导到我们所希望的方向上去。
以演化生物学、生态学和合作理论为基础，可以开发出一些治疗方法。演化–生态指数能够量化肿瘤的演化和生态动态变化，帮助我们预测肿瘤对治疗的反应，它们可以帮助我们区分有可能通过高剂量疗法根除的癌症，和采用适应性治疗等方法治疗效果更好的癌症。与其与癌症展开肉搏战，我们还可以发起一场情报战——利用来自各个方面的信息，做出明智的决策，控制癌症，并把癌症塑造成可以与我们共存的伙伴。
癌症是我们过往的一部分，几乎肯定也会是我们未来的一部分。但是，癌症的未来会怎样，这取决于我们。它可能仍旧是我们难以战胜的敌人，但我们也有可能改变它。我们有机会运用人类集体的智慧更好地控制癌症，让我们活得更久、更健康。要想把握住这个机会，需要跨学科合作、有效沟通和向着共同目标——找到更好的办法来控制癌症、造福人类——努力的紧迫感。癌症打破了所有的学科界限，它侵入了我们生活的方方面面，触及我们定居的每一个角落。因此，要了解其本质并找到治疗它的手段，我们需要一种彻底跨学科和通力合作的方法。
也许我们并不能消灭癌症，但是我们可以创造一个世界，在这个世界中，我们将癌症的治疗重新定义为对癌症的长期控制，并尽可能地把目光放在保护病人的生命和提高病人的生活质量上。这种未来就在我们能够抵达的前方。
[1] In 1972, just one year after signing the National Cancer Act, Richard Nixon signed an act creating a new national policy around an agricultural approach called “integrated pest management” T..D. Landis and R..K. Dumroese, “Integrated Pest Management — An Overview and Update,” Forest Nursery Notes (2014), https://www.researchgate.net/profile/R_Kasten_Dumroese /publication/272682105_Integrated_pest_management-an_overview_and _update/links/54ebbce10cf2082851be7e2b.pdf.
[2] The next strategy is to reduce the numbers of those pests, applying treatment to bring them back below the threshold where they are not doing too much damage D..G. Alston, The Integrated Pest Management (IPM) Concept (Logan: Utah State University Extension and Utah Plant Pest Diagnostic Laboratory, 2011).
[3] The evolution of resistance to chemotherapy has been a problem for every kind of drug that has ever been tried, including targeted therapies like EGFR blockades and HER2-targeted therapies Luis.A. Diaz.Jr. et.al., “The Molecular Evolution of Acquired Resistance to Targeted EGFR Blockade in Colorectal Cancers,” Nature 486, no..7404 (June.2012): 537–40; Rita Nahta et al., “Mechanisms of Disease: Understanding Resistance to HER2-Targeted Therapy in Human Breast Cancer,” Nature Clinical Practice Oncology 3, no..5 (May.2006): 269–80; Robert.A. Gatenby et.al., “Adaptive Therapy,” Cancer Research 69, no..11 (June.2009): 4894–903.
[4] adaptive therapy kept the mouse tumors under control Gatenby et.al., “Adaptive Therapy.”
[5] the adaptive therapy approach allowed these mice to “survive indefinitely with a small, reasonably stable tumor burden” Gatenby et.al., “Adaptive Therapy.”
[6] tumors could be controlled with a smaller and smaller dose as time went on Pedro.M. Enriquez-Navas et.al., “Exploiting Evolutionary Principles to Prolong Tumor Control in Preclinical Models of Breast Cancer,” Science Translational Medicine 8, no..327 (February.2016): 327ra24.
[7] more stable environments can select for cells that have slower life history strategies Aktipis et.al., “Life History Trade-Offs in Cancer Evolution.”
[8] As of October.2017, when Zhang and Gatenby’s pilot study was accepted for publication, only one of the eleven patients’ cancers had progressed Jingsong Zhang et.al., “Integrating Evolutionary Dynamics into Treatment of Metastatic Castrate-Resistant Prostate Cancer,” Nature Communications 8, no..1 (November.2017): 1816.
[9] Some five-year survival rates are extremely high, near 100.percent for early-stage thyroid cancer and between 60 and 85.percent for childhood leukemias, depending on the type, according to the American Cancer Society. R. L. Siegel, K..D. Miller, and A. Jemal, “Cancer Statistics, 2018,” CA: A Cancer Journal for Clinicians 68, no..1 (2018): 7–30.
[10] some studies suggest that patients can do just as well with palliative care (which is focused on improving patient quality of life and reducing pain) as with expensive and painful treatment that is aimed at curing the cancer Jennifer.S. Temel et al., “Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer,” New England Journal of Medicine 363, no..8 (August.2010): 733–42; Stephen R. Connor et al., “Comparing Hospice and Nonhospice Patient Survival among Patients Who Die within a Three-Year Window,” Journal of Pain and Symptom Management 33, no..3 (March.2007): 238–46.
[11] “Drug use causes drug resistance, a firestorm of drugs removes the competitors of the very things we fear: the cells and bugs we can’t kill” Andrew.F. Read, “The Selfish Germ,” PLoS Biology 15, no..7 (July.2017): e2003250.
[12] We established a set of principles for how to measure cancer’s evolvability, called the Evo-Index and Eco-Index Carlo.C. Maley et.al., “Classifying the Evolutionary and Ecological Features of Neoplasms,” Nature Reviews Cancer 17, no..10 (October.2017): 605–19.
[13] it often takes decades from the first mutations to finding cancer S. Jones et.al., “Comparative Lesion Sequencing Provides Insights into Tumor Evolution,” Proceedings of the National Academy of Sciences of the United States of America 105, no..11 (2008): 4283–88.
[14] one baby aspirin per day helped reduce the mutation rate by an order of magnitude Rumen.L. Kostadinov et.al., “NSAIDs Modulate Clonal Evolution in Barrett’s Esophagus,” PLoS Genetics 9, no..6 (June.2013): e1003553.
[15] multiple studies have shown that NSAIDs slow progression to esophageal cancer as well as many other cancers Jack Cuzick et.al., “Aspirin and Non-Steroidal Anti-Inflammatory Drugs for Cancer Prevention: An International Consensus Statement,” Lancet Oncology 10, no..5 (May 2009): 501–7; Enrico Flossmann, Peter.M. Rothwell, and British Doctors Aspirin Trial and the U.K.-TIA Aspirin Trial, “Effect of Aspirin on Long-Term Risk of Colorectal Cancer: Consistent Evidence from Randomised and Observational Studies,” Lancet 369, no..9573 (May.2007): 1603–13; Peter.M. Rothwell et.al., “Effect of Daily Aspirin on Long-Term Risk of Death due to Cancer: Analysis of Individual Patient Data from Randomised Trials,” Lancet 377, no..9759 (January.2011): 31–41; Thomas.L. Vaughan et.al., “Non-Steroidal Anti-Inflammatory Drugs and Risk of Neoplastic Progression in Barrett’s Oesophagus: A Prospective Study,” Lancet Oncology 6, no..12 (December.2005): 945–52, https://doi.org /10.1016/S1470-2045(05)70431-9.
[16] This may be because NSAIDs reduce the mutation rate directly Kostadinov et.al., “NSAIDs Modulate Clonal Evolution in Barrett’s Esophagus.”
[17] Gatenby and his colleagues found that they could decrease cell proliferation of resistant cells in Petri dishes and that the growth rate of resistant cell lines (compared to similar nonresistant cell lines) was lower in a mouse model with the administration of the ersatzdroges Kam et al., “Sweat but No Gain,” International Journal of Cancer 136, no. 4 (2015): E188–96.
[18] The size of the primary tumor was not affected, but by returning the tumor environment to a more pH neutral state, the metastases were significantly decreased — and this led to an improvement in survival for the mice receiving what Gatenby’s team called “bicarbonate therapy” Ian.F. Robey et.al., “Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases,” Cancer Research 69, no..6 (March.2009): 2260–68.
[19] When oxygen levels are low, cancer cells are more likely to invade and metastasize Erinn.B. Rankin and Amato.J. Giaccia, “Hypoxic Control of Metastasis,” Science 352, no..6282 (April.2016): 175–80.
[20] Studies suggest that normalizing the resource delivery to the tumor can actually reduce metastasis M. Mazzone et.al., “Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization,” Cell 136, no..5 (2009): 839–51.
[21] using low levels of antiangiogenic drugs (which help to regulate blood flow to the tumor) can improve response to treatments Yuhui Huang et al., “Vascular Normalization as an Emerging Strategy to Enhance Cancer Immunotherapy,” Cancer Research 73, no..10 (May.2013): 2943–48.
[22] It’s similar to what Winston Churchill said about democracy: that it is the worst form of government except for all those other forms that have been tried. Winston.S. Churchill, November.11, 1947, The International Churchill Society, https://winstonchurchill.org/resources/quotes/the-worst-form-of-government/.
[23] Many cancers have cells with mutations in TP53 Karen.H. Vousden and Xin Lu, “Live or Let Die: The Cell’s Response to p53,” Nature Reviews Cancer 2, no..8 (August.2002): 594–604.
[24] Some potential strategies for rebooting cellular self-control are restoring TP53 function when it is lost A..N. Bullock and A. R. Fersht, “Rescuing the Function of Mutant p53,” Nature Reviews Cancer 1, no..1 (October.2001): 68–76.
[25] elephant TP53 can restore normal p53 function and apoptosis in human osteoscarcoma cells Lisa.M. Abegglen et.al., “Abstract A25: Elephant p53 (EP53) Enhances and Restores p53-Mediated Apoptosis in Human and Canine Osteosarcoma,” Clinical Cancer Research 24, no..2 suppl.(January.2018): 48–49.
[26] reducing inflammation helps reduce the risk of cancer Kostadinov et.al., “NSAIDs Modulate Clonal Evolution in Barrett’s Esophagus.”
[27] By restoring the immune system’s ability to detect cellular cheaters, immune checkpoint blockade therapies have been successful at treating previously intractable cancers, including melanomas and lung cancers, in some patients Drew.M. Pardoll, “The Blockade of Immune Checkpoints in Cancer Immunotherapy,” Nature Reviews Cancer 12, no..4 (March.2012): 252–64; Suzanne.L. Topalian et.al., “Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer,” New England Journal of Medicine 366, no..26 (June.2012): 2443–54; F. Stephen Hodi et.al., “Improved Survival with Ipilimumab in Patients with Metastatic Melanoma,” New England Journal of Medicine 363, no..8 (August.2010): 711–23.
[28] cancer cells do still evolve resistance to immunotherapies Russell.W. Jenkins et.al., “Mechanisms of Resistance to Immune Checkpoint Inhibitors,” British Journal of Cancer 118, no..1 (January.2018): 9–16.
[29] interfering with adhesion in circulating cell clusters to hopefully reduce the likelihood of metastasis (since cell clusters have been found to be more likely to metastasize than single cells) Aceto et.al., “Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis.”
[30] Disruption to cooperative cellular signaling among cancer cells is another potential strategy for cancer control G. Jansen, R. Gatenby, and C..A. Aktipis, “Opinion: Control vs. Eradication; Applying Infectious Disease Treatment Strategies to Cancer,” Proceedings of the National Academy of Sciences of the United States of America 112, no..4 (2015): 937–38.
[31] Perhaps we should be searching for and using drugs that disrupt cell cooperation by interfering with cancer cell communication Jansen, Gatenby, and Aktipis, “Opinion: Control vs. Eradication.”
[32] Higher levels of plakoglobins are associated with worse patient outcomes Aceto et al., “Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis.”
[33] Interfering with public good production is one example of an intervention targeted at disrupting cancer cell cooperation John.W. Pepper, “Drugs That Target Pathogen Public Goods Are Robust against Evolved Drug Resis-tance,” Evolutionary Applications 5, no..7 (November.2012): 757–61.
[34] the late evolutionary biologist Stephen Jay Gould said, “I prefer the more martial view that death is the ultimate enemy — and I find nothing reproachable in those who rage mightily against the dying of the light.” Stephen.J. Gould, “The Median Isn’t the Message,” Discover 6, no..6 (1985): 40–42.
[35] Many researchers in the cancer community are working to identify the key par-ameters that should be used when we’re making strategic decisions about how to treat cancer Gatenby et.al., “Adaptive Therapy”; Maley et.al., “Classifying the Evolutionary and Ecological Features of Neoplasms.”; Elsa Hansen, Robert.J. Woods, and Andrew.F. Read, “How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient,” PLoS Biology 15, no..2 (2017): e2001110.
[36] This shift in our thinking allows us all to consider cancer as a chronic and manageable disease, which opens up new pathways for treating and preventing cancer Robert.A. Gatenby, “A Change of Strategy in the War on Cancer,” Nature 459, no..7246 (2009): 508–9; Sui Huang, “The War on Cancer: Lessons from the War on Terror,” Frontiers in Oncology 4 (October.2014): 293; Bryan Oronsky et.al., “The War on Cancer: A Military Perspective,” Frontiers in Oncology 4 (2014): 387.