Pragmatism and Chemoprevention


Taking an apple a day will not stop you from getting lung cancer if you are a heavy smoker, although if you have a  daily fruit intake there is good evidence that you are less likely to get it. Preventing cancer with a more proactive approach using drugs may save many lives, but is it be acceptable to a healthy public?

Drugs for Chemoprevention

Some drugs protect us from getting cancer. Taking chemoprevention agents early in high-risk individuals – eg with high risk of precancerous lesions in their lungs – will prevent them from going on to develop cancer later.

Treating this group of healthy, but high risk, patients will work for some; if it should be health policy is another matter.

Barriers to Drug Development

Developing drugs for cancer prevention is extremely difficult. We need to overcome certain hurdles to make an effective agent available to the general public.

Proving it has efficacy and prevents cancers and any related morbidity and mortality is one step. Also it should do no harm and and be acceptable to people who are not yet patients.

Some questions to be answered when developing new drugs to prevent cancer include:

  • How to select therapeutic targets and agents?
  • What is the risk/benefit analysis?
  • How do we select the proper cohorts for these interventions?
  • How do we recognise these agents when we encounter them?
  • How do we design the trials that show the most relevant endpoints?

It is a long and tortuous process that doesn’t always lead to return on investment.

Understanding Cancer Biology is Key

Getting to grips with the biology and understanding the mechanism of carcinogenesis is key to developing efficacious drugs.

Cancer is a complex group of diseases. Until we understand the things that go into the development of designated cancers it is quite hard to develop strategies across the board.

This means looking at preclinical models, examining observational studies that identify potential targets, and also finding studies done in cancers or other diseases that provide secondary endpoints that might provide clues as to what might be good candidate drugs.

The Cancer Model

Developing models of cancer progression is invaluable. Certain medications may only work at particular stages of cancer so timing of treatment is crucial role.

Cancer prevention is hampered as we are dealing with a disease yet to occur. This  temporal component makes targeting a specific abnormality in relation to when it occurs during the natural history of the disease vital. During early disease, an abnormality may be responsible for turning that cell into a cancer cell. Targeting this timepoint may give high efficacy. In late disease with many abnormalities the intervening may be more difficult with lower efficacy.

Chronic myeloid leukaemia is often seen as a paradigm for cancer prevention and treatment. In the initial stages, the Bcr-Abl is central to the abnormality of disease and effective therapeutic agents can target this abnormality. However as the disease progresses the Bcr-Abl mutation becomes is significant and additional abnormality develops. The efficacy of treatment radically diminishes in this lateral accelerated phase.

Efficacy of a drug is also affected by the number of contributory mutations to a particular type of cancer. If the target abnormality is driving disease, then the drug will be more efficacious than if the abnormality is one of a number of different drivers of disease.

Early diagnosis of cancer can be problematic, as patients may have no major symptoms. No visible abnormality may be detectable using diagnostic imaging techniques.

Which Studies are Best?

Animal models are used as efficacy indicators, but they may or may not reflect what happens in humans.

Observational epidemiology is fraught with the difficulty that the conclusions with respect to cancer prevention need to be validated through clinical trials. Many observational studies indicate diets rich in fruit and vegetables offer lung cancer protection and yet beta-carotene was found in one study to increase the risk of lung cancer in a cohort of smokers.

Observational epidemiology is an important tool to identify efficacious strategies, but it can be difficult to ascertain what is the active protective component.

Learning from Other Disciplines

Evidence for the chemoprevention potential of drugs can come from secondary endpoints of clinical trials in other diseases. In the MORE study of the effects of raloxifene on BMD and fractures in osteoporosis, it was found to reduce oestrogen receptor positive breast cancer in those women who took part in the study. The Star trial confirmed these results and showed that tamoxifen plus raloxifene treatment reduced breast cancer in postmenopausal women by 50%.

Similarly drugs used for other treatments may benefit chemoprevention. Nonsteroidals given for comorbid conditions reduce the non-infection inflammatory component of some cancers and slow progression.

Looking for Cancer Biomarkers

Good clinical biomarkers are useful as they:

  • Identify and validate a therapeutic drug.
  • Can be screened, and help optimise the candidate drug.
  •  Enhance our understanding of how the drug acts or how it works in combination therapies.
  •  Identify best target groups, predict response, therapeutics and toxic effects.
  • Distinguish who will benefit from treatment and serve as surrogate markers for clinical trials.

Having relevant endpoints for trials is crucial to interpretation of the evidence. Without an appropriate endpoint good drugs can be missed and ineffective drugs might be given too much attention.

Balance of Risk to Benefit

Analysing risk to benefit is one of the most important aspects of chemoprevention. The mantra is the higher the risk of the cohort the greater is the toxicity that the potential treatment can have. There is no magic number or no magic calculation of how to determine risk to benefit for a cancer prevention medicine. The toxicity profile of the intended dose is vital to assessing risk. Pharmacologic doses of agents may be very different from replacement doses.

Long-term follow up data is crucial to identifying the true toxicity profile of any given drug. In the case of the cox-2 inhibitor celocoxib, unacceptable cardiovascular side-effects surfaced after 12-18 months use. The drug was approved when only short-term studies were presented to the regulatory authority.

To optimise the benefit of chemoprevention it is vital to identify those people who really need interventions to prevent their cancer. In the case of lung cancer, defining cohorts for measuring intervention efficacy is crucial. For example, the natural history of the disease is different in smokers and former smokers.

We can’t tell who is at highest risk and we really don’t understand carcinogenesis in most target organs. But in some diseases high risk patients can be identified. Oral dysplasia plus loss of heterogenicity at specific loci is a useful biomarker for oral cancer.

Even when efficacious strategies are developed compliance can be a problem, the costs are quite high and there are psychological issues, such as the perception in the US that Tamoxifen is not a safe drug.

Deciding on the endpoint of a study is fraught with difficulty as intermediate endpoints that are surrogates for cancer incidence need to be selected. The challenge is to find something that is present now that can be modulated and that will correlate with the prevalence of cancer sometime in the future.

Conclusion

Despite these hurdles chemoprevention agents will prevent cancer from occurring and it can change management. The aim of healthcare is to shift care from an advanced to a preclinical setting. This reduces resources needed and shifts care from specialist invasive interventions to treating early preclinical disease.

Drugs used to prevent cancers will reduce morbidity and mortality. But will enough well people take these medicines before they become ill to make it worthwhile? Compliance and perceiving benefit are key barriers to their usefulness.

Advertisements

2 Responses to “Pragmatism and Chemoprevention”

  1. Very interested in your opinion of chemoprevention drugs & their effectiveness. Is there anything to counter the threat of prostate or bowel cancers?

    • Tamoxifen is the big one so far in this area for breast cancer.

      For Prostate Cancer it is thought finasteride and the tyrosine kinase inhibitors (TKI) may be of benefit. TKI Genestein is naturally occurring in Soy and in Chinese populations there is very low prostate and breast cancer incidence. So do you take the soy source or the medication?

      Curcumin for colorectal cancer. It is a constituent of spice cumin.

      In the past, all kinds of claims where made for vit E (tocopherol), selenium, vit D, etc.. as chemopreventive agents.

      Proving the usefulness of a cancer chemopreventive agent may be complicated by the fact that we lump all cancers together and individual agents may only work in some individuals with specific types of colon cancer for eg with specific disease mechanisms at play or at specific points in the disease process.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: