12 Introduction to Cancer Therapy

12.1 Tumour Growth

In the first paragraph we will talk about tumour growth, the effects of cancer chemotherapy and as a first group of anti cancer agents, we will look at alkylating agents.

For cancer treatment, it is important to understand how fast or slow tumours grow. We shall start with some theoretical considerations: theoretically during each cell division cycle, the number of cells doubles (Figure 10.1). Looking at the mass of a tumour and the average size of cells we can estimate the number of cells in a tumour. Based on those estimates we can assume that the cancer cells would have had to divide at least 30 times before a tumour reaches the typical size at which it would be diagnosed (Figure 12.1).22 Once diagnosed it would take only a mass increase equivalent to about 10 additional doublings before a tumour might reach a volume at which some patients could already die if untreated. Importantly, in practice, different tumours show very different average doubling times. For example Burkitt’s lymphoma can present as a very rapidly growing tumour with doubling times of about 1 per day, whereas at the other end of the scale, many breast cancer can have doubling times of about once per 100 days.

Tumour diameter as a function of tumour cell population doublings.

Figure 12.1: Tumour diameter as a function of tumour cell population doublings.

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Table 10.1 Doubling times for selected cancers. Doubling times can vary enormously between different tumour types.Using x-rays a tumour is first visible at a size of a few mm and is palpable at a diameter of about 1 cm. At close to a diameter of 10 cm, patients usually die (see Figure 12.1) (add ref).

Cancer Theoretical doubling time (days)
Burkitt’s lymphoma 1
Hodgkins’s lymphoma 4-5
Testicular cancer 5-6
Colon cancer 80
Breast cancer 100

However, these are theoretical considerations, because in these calculations, we have for example to take into account tumour vascularization (see chapter XXX).

12.1.1 Factors affecting Tumour Growth

Which are the factors affecting tumour growth? Not all cells of a tumour proliferate (Figure 12.2). The dark coloured part in the middle of the tumour is the necrotic centre. In this region cells are dying or are already dead. Surrounding the necrotic centre is the zone of cell stasis, which is low in oxygen. Without oxygen supply and nutrients tumours don’t grow in this region. This part of the tumour shows a proliferating zone. In this zone, oxygen levels are high because the tumour developed a capillary network (shown in red). The so-called invasive zone (shown in purple) is at the border of the tumour.

Schematic presentation of a tumour showing the distinct regions that contribute to its growth

Figure 12.2: Schematic presentation of a tumour showing the distinct regions that contribute to its growth

In addition, tumour growth also depends on the size of the tumour (Table 10.2). As bigger the tumour is, as longer it takes for its mass to double. In reality not all tumour cells proliferate.

Table 10.2 Size dependence of tumour growth (add ref).

Tumour size [mg] Mass doubling time [days] Growth fraction [%] Cell cycle time [days]
2 0.5 100 -
25 0.7 61 0.48
250 1.2 40 0.75
700 1.8 25 0.61
1300 2.7 19 0.64
5000 7.5 7 0.69

12.2 A brief History of Cancer Treatment

Cancer chemotherapy refers to the use of cytotoxic drugs in the treatment of cancer. The era of chemotherapy began in the 1940 with the use of nitrogen mustards we will talk about in a moment. Some historical observations have been made, which are listed here:

  • Chemicals exist that can destroy or kill cancer cells,

  • Unfortunately, chemotherapy also impacts on dividing non-cancer cells leading to undesired side effects,

  • Chemicals that kill cancer cells poison fast growing tumour cells.

In conclusion, cancer chemotherapy is most effective against fast growing tumours.

12.3 Drug Efficacy Versus Tumour Regrowth

For successful cancer treatment one has to kill or destroy the majority of cancer cells to have an effect on tumour growth. The data shown in Figure 12.3 are from animal models. The black curve represents uninhibited tumour growth leading to the animal’s death after just a few days. The green curve shows tumour growth in the presence of a cancer drug that kills 50% of cancer cells. With 75% of tumour cells killed, you would still not see the tumour to shrink. To have a significant impact on tumour growth, you really only obtain a reduction in the tumour when you aim for killing the majority, or better all cancer cells.

Tumour growth in the presence of cancer drugs of varying efficacy. Efficient tumour reduction or preferably complete tumour regression can only be achieved by killing all cancer cells.

Figure 12.3: Tumour growth in the presence of cancer drugs of varying efficacy. Efficient tumour reduction or preferably complete tumour regression can only be achieved by killing all cancer cells.

12.4 Somatic Evolution and Cancer Therapy

As discussed in more detail in previously, somatic evolution is an important concept in the development of cancer (Figure 12.4). It explains, why it is so important to kill all cancer cells, if possible. There is a variation in the population of cancer cells, which is heritable. When a cancer cell divides, both daughter cells inherit the genetic and epigenetic abnormalities of the parent cell (indicated by the two yellow daughter cell for example), but may also acquire new abnormalities (as shown by the green and yellow daughter cells here). This variation affects survival and reproduction (fitness).

Drug treatment acts as a form of artificial selection, by killing sensitive cancer cells, but leaving a few resistant cells alive (in this case the cell coloured in pink survives). Often, tumours will regrow from those resistant cells. In addition, the new tumour will be resistant to the initial treatment. In a tumour with high heterogeneity, the chances of occurrence of cells with resistance are higher than in a tumour with low heterogeneity.

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Excursion Box: Somatic evolution is the accumulation of mutations in the cells of a body during a lifetime, and the effects of those mutations on the fitness of the cells. In different tumour subtypes, cells within the tumour population exhibit functional heterogeneity, and tumours are formed from cells with various proliferative and differentiate capacities. This functional heterogeneity among cancer cells has led to the creation of at least two models, which have been put forward to account for heterogeneity and differences in tumour-regenerative capacity: the cancer stem cell (CSC) and clonal evolution models.

The cancer stem cell model refers to a subset of tumour cells that have the ability to self-renew and are able to generate the diverse tumour cells. These cells have been termed cancer stem cells to reflect their stem-like properties. One implication of the CSC model and the existence of CSCs is that the tumour population is hierarchically arranged with CSCs lying at the apex of the hierarchy.

The clonal evolution model postulates that mutant tumour cells with a growth advantage are selected and expanded. Cells in the dominant population have a similar potential for initiating tumour growth. These two models are not mutually exclusive, as CSCs itself undergoes clonal evolution. Thus, the secondary more dominant CSCs may emerge, if a mutation confers more aggressive properties.

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Model of heterogeneous tumour cells undergoing treatment with a cancer drug. A single surviving tumour cell coloured in light purple may be sufficient to lead to renewed growth of the tumour, which in turn may again develop further tumour heterogeneity.

Figure 12.4: Model of heterogeneous tumour cells undergoing treatment with a cancer drug. A single surviving tumour cell coloured in light purple may be sufficient to lead to renewed growth of the tumour, which in turn may again develop further tumour heterogeneity.

12.5 Consequences for Cancer Chemotherapy

We can now draw some conclusions from our observations on tumour growth, tumour heterogeneity and chemotherapy. A tumour contains dividing as well as resting cells, but chemotherapy predominantly kills dividing cells. The consequences of targeting dividing cells are that non-tumour cells that also divide are equally targeted including the bone marrow, the gastrointestinal mucosa and hair follicles. The model of Cancer Stem Cells introduced perviously postulates that there may always be a reservoir of resting cells. Therefore, the aim is to kill all cancer cells. If we do not succeed in killing all cancer cells, the tumour has a high probability of growing back. One option would be to apply high drug doses frequently, but drugs can induce serious side effects and the patient may become very ill. In this respect chemotherapy is limited by drug toxicity. We also have to keep in mind that drug treatment must continue after remission. As said previously even a very tiny number of surviving cells may or will grow leading to a new resistant tumour. Remember: 10 to 8 cells are barely detectable, but tumour cells may still be there.

12.6 Managing and Minimizing Drug Toxicity

Drug toxicity has to be minimised and properly managed. Side effects from drug treatment can either be acute, medium term or long term. They can also occur at different times during chemotherapy (Figure 12.5). For example, in oncology, the term nadir commonly refers to the lowest level of a blood cell count while a patient is undergoing chemotherapy. The nadir for each blood cell type occurs at different times. For example, the nadir for white blood cells and platelets normally occurs around day seven to 14 following the last day of treatment. A diagnosis of neutropenic nadir after chemotherapy typically lasts seven to ten days. Therefore, drug administration is given in cycles over extended time periods, including breaks to allow the body to recover. Many cancer agents are administered in combination with other drugs, which may differ in their side effect profile and time scales. Therefore, the administration of drug combinations has to be optimised. In case drug combinations act synergistically, one can reduce the drug dose and thus decrease toxic side effects. During our lectures we will talk about the options we have to manage and minimise side effects for patients.

 Occurrence and duration of acute, medium term and long term side effects after cancer drug treatment.

Figure 12.5: Occurrence and duration of acute, medium term and long term side effects after cancer drug treatment.

Summary

In summary we have looked at tumour growth and we understood the effects of cancer chemotherapy. We now come to the interesting part of this lecture, how to fight, treat or at least delay cancer in patients. It should be mentioned that there are different options for cancer treatment. Surgery, which can also be combined with radiation therapy and chemotherapy. If surgery is difficult or not possible any more the next choice would be radiation therapy. If these two treatment options are exhausted, chemotherapy will be used. Often chemotherapy is palliative, meaning that a patient’s live can only be prolonged, eventually the patient will die.

Bibliography

1. Article about tumour growth with different tumours listed in table

2. Tumour size

3. History of cancer treatment

  1. Add paper on tumour doubling times

  1. This number may well be quite a bit higher as both, cell proliferation and cell death can occur simultaneously.↩︎