What is the “natural history of cancer”?

The term natural history of cancer refers to the course of the disease from beginning to end, if nothing is done and no intervention is made.

A starting theoretical model

For breast cancer, we have long adhered to a linear, mechanistic theory of cancer progression, as shown in the diagram below.

This is known as the Halstedian scheme, after the North American surgeon William Halsted (1852-1922), who theorized this convenient, intuitive vision.
But knowledge is evolving.

It’s not so simple

And in fact, cancers exhibit a wide spectrum of clinical behavior; at one end of the spectrum are aggressive, rapidly progressing tumors, and at the other are indolent, slowly progressing tumors or no progression at all.
The former (e.g. anaplastic thyroid carcinoma and pancreatic adenocarcinoma, aggressive forms of breast tumour) are often unresectable or metastatic from the outset at the time of detection, and often have a poor prognosis.
On the other hand, indolent tumors (for example, certain small papillary tumors of the thyroid or prostate, and many small, low-stage breast tumors detected during routine mammography) may remain asymptomatic and not progress during the patient’s lifetime. These indolent tumours, if never diagnosed, would not progress to the point of causing symptoms or death; they are referred to as “overdiagnosis“.
Overdiagnosis has been documented for small tumors of the prostate, thyroid, breast and many other organs.
Since over-diagnosed tumors are not at risk, their treatment is unnecessary, exposing patients to the risks and toxicity of interventions without benefit.

Unfortunately, there are no reliable techniques for differentiating the subset that remains indolent from tumors that may progress; consequently, all cases of detected tumors are definitively treated with surgical resection and/or radiotherapy.
The mechanisms underlying the indolent behavior of tumors, which are probably largely immune-based, are currently unknown.

Another model

The traditional model is therefore outdated. It is far too simple to properly represent the multitude of diseases currently referred to as “cancer”.

In the 1960s and 1970s, American surgeon Bernard Fisher and Italian oncologist Umberto Veronesi challenged Halsted’s view of the orderly progression of cancer. They hypothesized that breast cancer could be a systemic disease from the outset: tumor cells could be disseminated throughout the body by the time of detection.
Recent research in cancer genomics suggests that Fisher and Veronesi’s hypothesis extends beyond breast cancer. In an analysis of 118 biopsies from 23 colorectal cancer patients with distant metastases, dissemination was found to occur long before the primary tumor was large enough to be clinically detectable.
Hu Z, Ding J, Ma Z, Sun R, Seoane JA, Scott Shaffer J, et al. Quantitative evidence for early metastatic seeding in colorectal cancer. Nat Genet. 2019;51:1113-22.
These aggressive cancers, “born to be bad”, would escape any practicable early detection effort, yet they are the ones most likely to cause death.

Cancers at the other end of the growth spectrum became massively detectable with the advent of widespread prostate cancer screening in the USA in the 1990s. Some localized prostate cancers grow so slowly that they are not meant to cause symptoms until the patient dies due to competing risks of death, particularly in older men.
Welch HG, Albertsen PC, Nease RF, Bubolz TA, Wasson JH. Estimating treatment benefits for the elderly: the effect of competing risks. Ann Intern Med. 1996;124:577-84.

What’s more, some lesions that are cancerous under the microscope may not develop at all. The same phenomenon has been observed in randomized trials of lung cancer screening by chest radiography.
Black WC. Overdiagnosis: an underrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst. 2000;92:1280-2.

Subsequent observations suggesting that some breast, thyroid and kidney cancers regress have added to the complexity of the situation.
In other words, certain breast, colon and lung cancers are already systemic when detectable, while others are not destined to metastasize.

Observations, research, studies, findings in clinical practice and the knowledge of modern oncology suggest a different, more complex and heterogeneous contemporary pattern of cancer progression.

Screenshot

It’s more like a bush of possibilities, with some cancers progressing very quickly and becoming metastatic and fatal from the outset, others progressing very slowly and not progressing at all, or even regressing, and others evolving quietly, one day giving rise to a clinical symptom that will lead the patient to seek advice. 

In the FAQ https://cancer-rose.fr/en/2021/10/23/how-does-a-cancer-develop/, we explain how screening works on each different form of cancer.

For regressive cancers: Regression is rarely observed, not because it’s rare, but because it’s difficult to observe, because as soon as a cancer is detected, it’s logically treated. So there are few opportunities to actually observe the phenomenon.
For example, it has been observed in women who were about to undergo surgery for their cancer, but whose surgery was postponed due to the onset of another disease that was more urgent to treat. These cases of regression do exist, and not only for breast cancer.
* Tokunaga E, Okano S, Nakashima Y, Yamashita N, Tanaka K, Akiyoshi S, et al. Spontaneous regression of breast cancer with axillary lymph node metastasis: a case report and review of literature. Int J Clin Exp Pathol. 2014; 7(7): 4371-80.
* Onuigbo WIB. Spontaneous regression of breast carcinoma: review of English publications from 1753 to 1897. Oncol Rev. Oct 2012; 6 (2): e22.
* Ricci SB, Cerchiari U. Spontaneous regression of malignant tumors: Importance of the immune system and other factors (Review). Oncol Lett. Nov 2010; 1(6): 941-5.

The natural history of cancer is therefore extremely complex and unpredictable, and cannot be summed up in misleading pink campaign slogans such as “the smaller the better”. This adage is long-forgotten and completely wrong.

little but ancient ; ductal carcinoma, no change in 18 years
cancer, 7 months between both mammographies

1987/1988/1989/1998 – cancer regression and re-apparition 10 years later

References

References :

Pandey A, Linxweiler M, Kuo F, Marti JL, Roman B, Ehdaie B, Vos JL, Morris LGT. Patterns of immune equilibrium and escape in indolent and progressing tumors. Cancer Cell. 2023 Aug 14;41(8):1389-1391. doi: 10.1016/j.ccell.2023.06.003. Epub 2023 Jul 6. PMID: 37419120.


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