4 Is cancer a single disease?

Given the frequency of a cancer diagnoses most, members of the public will have encountered ‘cancer’ in some form: hearing about a friend or neighbour, encountering it in the family, or learning about public figures and celebrities in the news or social media. Frequently, the diagnosis of cancer is linked to troubling reports of challenging treatments and, all too often, poor outcomes.

These encounters paint a dramatic picture of a challenging disease but it is worth exploring in more depth whether this is the case uniformly. While there is, in the public perception of the disease, an awareness that different types of cancer do exist (e.g. for different organs) there is often less understanding of what factors affect an individuals actual clinical prognosis after a cancer diagnosis, i.e. the likely course or outcome of the disease. In the next sections we will examine the role of two of the main factors that contribute to a clinicians assessment of prognosis, i.e. tumour type and stage.

4.1 Survival rates for different types of cancers

It is striking that when measuring therapeutic success against cancer we typically do not talk about ‘cure’ but ‘survival,’ e.g. as survival rate (i.e. the percentage of patients who are alive for a given period) or the survival time (i.e. the period of time patients are typically alive after diagnosis). We have seen that for cancer around

the ‘5 year survival.’ When comparing the survival rates for various forms of cancer (Figure 4.1) we note that these can in fact vary widely. While for some forms of cancer, e.g. testicular cancer, 98 % of patients are still alive 5 years after diagnosis for other cancers the prognosis is much poorer; with only 10% of patients diagnosed with lung cancer or 3% of pancreatic cancer patients are surviving for this period of time. Furthermore, dramatic differences exist also when we compare survival of particular cancer types over time (i.e. 1, 5, 10 year survival). While for some cancers such as malignant melanoma there is less than 10% difference between those that survive for on year compared to those that survive 10 years, for other cancers a much smaller proportion of patients survive for long, e.g. in brain cancer less than a third of those that survived for one year are still alive after 10 years. Thus there is in many cases a significant risk for cancer patients eventually succumbing to their disease even after initial successful treatment. In order to be able to compare treatments more effectively it is thus often more practical to consider surrogate endpoints8 for therapeutic success such as ‘5-year-survival.’ While these figures highlight the importance of differentiating between different types of cancer, they only show part of the story. They only represent an average over a range of possible therapeutic outcomes.

Cancer incidence (disk size) and survival rates for different cancer types (source: CRUK)

Figure 4.1: Cancer incidence (disk size) and survival rates for different cancer types (source: CRUK)

One of the questions one might ask is why we do see these differences in terms of survival? It is noticeable that those cancers with relatively best prognosis (testis, breast, melanoma) are easily accessible to examination while for some of the most challenging cancers (pancreas, lung, brain) this is much more difficult to achieve. So part of the difference in prognosis might be explained how easy it is to discover these cancers and, consequently, how early they would be diagnosed.

4.2 Why is early diagnosis so important?

The natural progression of solid cancers, i.e. of those forming solid tumours and metastases, is critically important in determining prognosis after a cancer diagnosis. All tumours start off with a few cells that have undergone a partial transformation, i.e. they have acquired some mutations or ‘heritable changes’ which change their phenotype and growth pattern (Figure 4.2)).

At this point these cells may simply show some excessive local growth (hyperplasia) but otherwise appear normal. Such cell clusters can continue to change and cells start to look microscopically abnormal (dysplasia). At this point these cells do not necessarily become cancer but once the cells start to acquire a more malignant phenotype and start to expand their growth beyond the natural confinement of this tissue (e.g. basal membrane) they are clearly cancerous (carcinoma in situ). As the disease progresses the cancer increasingly ‘invades’ neighbouring tissues, eventually gaining access to lymphatic and blood vessels (invasive cancer). This change brings with it a risk of cancer cells being dislodged and washed away into the blood stream to eventually settle in another organ and giving rise to metastatic tumours. Once this has happened the cancer has changed from a local disease to a systemic disease. This dramatically changes the options and requirements for treatment and consequently the clinical prognosis.

Natural progression of cancer (tumour)

Figure 4.2: Natural progression of cancer (tumour)

4.3 Stage, Grade and Prognosis

Currently individual tumours are characterized and staged using a number of diagnostic techniques. The aim is for doctors to be able to assess to what extend the tumour has remained a local disease or whether it has started to affect neighbouring tissue (invasion) or even remote parts of the body (metastasis). Understanding this will allow the most suitable therapeutic options to be chosen. It also gives some indication on the patients prognosis, i.e. the most likely progression of the disease.

4.3.1 Cancer Stage

Key factors that typically determine the stage relate to a) the nature (cell type) and size of the primary tumour b) to what extend it has been contained within the natural tissue boundaries c) whether some cancer cells have been carried away and have lodged in local draining lymph nodes or have potentially already been carried further and have started to develop secondary tumours (metastases) in other parts of the body. Depending on the specific combination of these parameters a patients cancer is categorised into different stages, typically Stage I - IV with stage I describing a disease apparently limited to local proliferation only and stage IV a clinical situation where remote tumours (metastases) have been found.

This information is also captured in the T(umour), N(ode), M(etastasis) staging system whereby the stage is denoted using indices e.g. T1N0M0 would denote a small tumour without lymph node involvement or metastasis, whereas T4N3M1 would represent a large tumour that has spread to multiple lymph nodes and has already developed metastases. Example: Progression of Breast Cancer and Staging

These changes form a local to a systemic disease are reflected in the clinical staging typically assigned on cancer diagnosis is illustrated below for breast cancer (Figure 4.3):9

Stage 0

  • Carcinoma in situ
  • Abnormal cells
  • Developed in breast specific tissues *Duct, lobe, nipple
  • Non-invasive

Stage I

  • Tumour formed
  • Invasive (potential lymph node involvement)

Stage II

  • Size increased, more lymph nodes

Stage III

  • Spread to further regional LN
  • Larger tumour
  • Invasion into neighbouring tissue

Stage IV

  • Metastasis - spread to other organs
  • Typical organs for metastasis
    • Bone, Lungs, Liver, Brain

More advanced cancer has a worse prognosis - one important reason for this is that more advances cancers are in general more malignant but also that the chances of an early though not yet detectable metastasis increase.

Illustration of key changes with different clinical tumour stages in breat cancer (0-IV).

Figure 4.3: Illustration of key changes with different clinical tumour stages in breat cancer (0-IV).

4.3.2 Cancer Grade

While typical definition of cancer stage is based on clinical observations of the cancer in the body, in contrast, the description of grade is a histological / cytological description that compares the microscopical appearance of the majority of tumour cells with that of the normal, fully differentiated cells in that tissue. These observations will compare level of proliferation and invasive tendencies with grade I describing well differentiated cells/tissue and slow growing cells and grade III undifferentiated rapidly dividing cells.10

4.3.3 Prognosis

In general the prognosis is linked to the current clinical stage of the cancer (Stage I - IV, TNM) and histological appearance of the tumour (Grade I - III); these describe how far a tumour has progressed from local to systemic disease and, based on the histology, the likely rate of further progression. These principles apply accross the board although the specifics will always depend on the particular cancer type.

The grade of a tumour more a tumour resembles the functional tissue in terms of cells and histological structure the slower the progression of the tumour will typically be; typically this tumour is less aggressive and linked to a better prognosis.

The stage of the tumour is key to determining the best therapy for the patient. In almost all cases where the tumour is at an early stage surgery will be the first option. Removal of the tumour and potentially affected lymph nodes will also allow detailed histological analysis to assess the risk of a spread beyond the areas treated by surgery. In cases where it is too difficult to surgically remove the tumour or where it is desirable to treat prophylactic the neighbouring areas in a limited fashion, e.g. to reduce risk of local recurrence, then localised radiotherapy may be offered.

When the tumour has metastasised or there is a risk that it has spread beyond the local area systemic (chemo)therapy will typically be used as therapy or in a prophylactic context (adjuvant therapy). As our understanding of the molecular pathology of cancer improves the importance of molecular characterisation of tumours increases, e.g. to establish whether they carry the antigens used for targeting, or whether they are amenable to certain types of therapy.

For example, in breast cancer patients the tumour will undergo histological examination to determine the role of specific cell proteins that have been identified as being key drivers of specific types of breast cancer, i.e. oestrogen, progesterone, Her2/EGFR. Knowledge of the presence/absence of these disease drivers will allow selection of more targeted therapies. These type of molecular descriptors of a disease state are known as {index biomarkers} biomarkers and play an increasing role in cancer therapy.

4.4 Summary

Observations on cancer so far:

  • Caused by ‘abnormal’ cells
  • Prognosis affected by progression (stage)
  • Gradual progression from local to systemic disease

How do cells become ‘abnormal?’

  • Risk factors affect likelihood of getting cancer
  • Environmental risk factors, e.g. UV, smoking
  • Some cancers ‘run in families’
  • Incidence increases with age
  • Disease characterised by excessive cell growth

  1. The expression surrogate endpoints describes a clinical sign or parameter that typically for reasons of practicability is used instead of another more difficult measure to judge the effects of treatment.↩︎

  2. source↩︎

  3. Tissues are typically replenished by adult stem cells that produce progenitor cells that in turn produce fully differentiated cells. In general the ability of cells to divide rapidly decreases as they become more differentiated; it is possible that the different levels of differentiation may also link to the observation of cancer stem cells.↩︎