Advancing cancer in the prostate

By Dr HO GWO FUANG

A look at the treatment landscape of advanced prostate cancer.

Few outside the world of oncology (oncology is the study of cancer) realise that 2001 was a momentous year in the development of cancer treatment.

In May 2001, the US Food and Drug Association (FDA) approved the drug imatinib for the treatment of chronic myeloid leukaemia, heralding the age of “targeted therapy”.

Targetted therapy utilises so-called “magic bullets” designed to target tumour cells with greater accuracy and fewer side effects. An explosion of new drugs has been developed since then for various tumour types, for example, erlotinib, gefitinib, bevacizumab and cetuximab for lung cancers; sunitinib, sorafenib and temsirolimus for kidney cancers; and trastuzumab and lapatinib for breast cancers.

The use of chemotherapy for treatment of cancers has gone through a few eureka! moments.

The very first chemotherapy agent, nitrogen mustard, was originally used as a chemical warfare agent in the First World War. It was subsequently found that soldiers and ordinary citizens exposed to the agent were found to have low white blood cell counts.

Further experiments of the agent on lymphoma patients led to remarkable, albeit short-lived, improvement in their cancers. Since then, a few plant extracts (eg from the periwinkle plant, Pacific Yew tree), antibiotics (from a few strains of fungus) and heavy metal (eg platinum-analogues) were found to have anti-tumour activities.

In 1973, an Italian professor, Gianni Bonadonna, demonstrated that the administration of chemotherapy after a complete surgical excision of lymph node-positive breast cancer significantly improved the chance of cure, and this was proof of the concept of “adjuvant therapy”.

For treatment of advanced prostate cancer, a momentous moment occured in 1941 when Dr Charles Huggins, a Canadian-born American urologist working in the University of Chicago, in collaboration with his students Clarence Hodges and William Wallace Scott, demonstrated that androgens (male sex hormones) fuel the growth of prostate cancers, and that androgen-deprivation therapy could slow or halt that growth.

It was a groundbreaking discovery, and earned Dr Huggins a Nobel Prize for medicine in 1966. This remains the cornerstone for the treatment of advanced prostate cancer today.

However, 60 years on, prostate cancer remains the second-leading cause of cancer-related death among men in the US.

This is because after a certain period of time (on average, 12 to 18 months), many prostate cancers become resistant to hormone manipulation, and start to grow again. These kind of prostate cancers, called “hormone refractory prostate cancers” remain difficult to treat.

Despite advancement in chemotherapy for other cancer types, little progress was made in the chemotherapy for advanced prostate cancer before 2004.

Only two drugs were approved by the US FDA for the treatment of prostate cancer in that period: estramustine (1981) and mitoxantrone (1996), and none was shown to improve the length of survival in patients.

In 2004, two reports, by Ian Tannock of Princess Margaret Hospital in Canada and Daniel Petrylak in New York, for the first time showed that a chemotherapy agent prolonged the survival of advanced prostate cancer patients, and established docetaxel as the first-choice chemotherapy agent.

Docetaxel, like many conventional chemotherapy agents, has certain side-effects, and requires careful monitoring by both patients and physicians. This remains, however, a momentous step in the history of advanced prostate cancer treatment.

Where else should one go in pursuit of the next breakthrough?

We have realised for a long time that it is unlikely that there will be one cure for cancers. Such a cure, if any, may only be achieved by multiple small, incremental steps. In the age of molecular medicine, even a dedicated oncologist may find it difficult to keep up with all the latest developments and new findings in cancer therapies.

The number of new agents being tested in the past five years far exceeds those tested in the decade before that. Although this is good, as opposed to many more years in the doldrums, one feels a “cure” for advanced prostate cancer may still not be on the horizon for some time.

There have been small, incremental steps made in treating advanced prostate cancers. These include:

1. Proof that “hormone refractory” prostate cancer may not be completely “hormone refractory” after all, as agents like abiraterone, which is a potent blocker of many forms of male sex hormones, was shown to be effective in some patients.

2. Evidence that targeting the “tumour micro-environment” rather than just the cancer cells may also be beneficial, with agents like zoledronic acid that reduces bone pain and complications, and experimental agents such as atrasentan (that target blood vessels) and DN-101 (an activated form of vitamin D) showing early promise.

3. Immunotherapy – stimulating the body’s own natural defence mechanisms to fight cancer – has a core group of believers. However, it has seen many false dawns. The data in advanced prostate cancer is still immature, and any early enthusiasm may be replaced by disappointment when the results of larger studies are available.

Recalling the days when I was still a specialist registrar at the Royal Marsden Hospital in London, we were involved in testing one of these vaccines, and it gave fascinating insights into the world of immunotherapy.

The future, however, is still fraught with difficulties, and recently one of these trials was halted due to safety concerns.

However, one remains hopeful that more wisdom will be gained with the continuous hard work and dedication of all the health professionals and patients involved in research, and we will continue to make “small, incremental steps” in the pursuit of a “cure”.

- THE STAR