Dr Jim Duthie, Our #EMJExpert, Answers Your Questions for Blue September

In support of Blue September, an annual campaign designed to raise global awareness for male related cancers, we invited world-renowned urologist Dr Jim Duthie to answer your questions on the subject as part of an ‘Ask the Expert’ session. We would like to take this opportunity to thank our readers for their questions, and for their ongoing support of this fantastic cause. For more information on our #EMJExpert and his knowledge on the subject, view our previous blog here. Additionally, for more information on Blue September, visit their website here.

If bladder cancer comes back after chemotherapy there are currently not many effective treatment options that doctors can offer. What are the main treatments that are currently being researched and have there been any promising advancements recently?

Bladder cancer that returns after chemotherapy remains a disease that is difficult to treat. A combination of the chemotherapy drugs cisplatin and gemcitabine is at present the most safe and effective treatment for metastatic bladder cancer, but is rarely a long-term cure. If the cancer returns, there is only one treatment that has been shown to have any benefit on top of this combination in real-life trials, which is vinflunine. The benefits of vinflunine are marginal, and it has not been widely used for this reason. The good news is that a number of new treatment pathways are currently being investigated. These include drugs that target cellular proteins that prevent cancer cells from dying, and studies of other proteins that may be future drug targets, both for destroying cancer cells and for making cancer cells more sensitive to radiation therapy. As with all new drug treatments, it takes several years to develop the drugs and then prove that they are safe and effective.

What symptoms and side effects are most commonly seen as a result of testicular cancer treatment, and what progress has been made in clinical trials to ameliorate these?

The side effects of treatment in testicular cancer will be related to which of the range of treatments are required. Except in extraordinary circumstances, men will need to have the affected testis removed. After that, chemotherapy, abdominal (retroperitoneal) surgery, and less commonly radiation therapy may be given, all with their own potential side effects.

Removal of a testicle is usually a relatively minor procedure requiring a short general anaesthetic, and patients can often go home the same day. In nearly all cases, sperm and testosterone production are unchanged, as the remaining testis can cope on its own. Often the cancerous testis has not been functioning properly anyway. In rare cases, fertility treatment or hormone replacement may be needed. A silicone testicular prosthesis can be placed if desired, but many men find that these do not look or feel natural.

If chemotherapy is required, it comes with risks of nausea, temporary hair loss, skin conditions, and may affect fertility at least temporarily. Chemotherapy is usually relatively well tolerated, as the men tend to be young and otherwise healthy. If the cancer is more advanced, more intensive chemotherapy may be required, including bleomycin that may cause lung damage, although the relationship is not fully understood. Radiation therapy has a diminishing role in testicular cancer, and so will not be focussed on here. However, it is still occasionally used in unusual circumstances.

Abdominal surgery to remove the lymph nodes in the abdomen, or retroperitoneal lymph node dissection (RPLND) is not commonly required, but has a role in specific circumstances where the tumour, which has spread to the abdomen, may be present after chemotherapy. Along with the usual risks of major abdominal surgery (bleeding, infection, bowel injury), there is a risk of damaging the nerves that allow the man to ejaculate semen which therefore affects fertility.

In terms of advances in reducing the negative effects of treatment, there has been steady incremental progress in treating infertility related to surgery and chemotherapy, including sperm banking prior to treatment if this is required, and in reducing side effects from chemotherapy. The major advance in RPLND was the development of anatomical templates which mapped out areas of the abdomen where tissue could be safely left behind, preventing a loss of ejaculatory function but not leaving cancer behind. There is now a ‘nerve-sparing’ procedure performed at some centres that involves delicately peeling tissue off the nerves themselves, further reducing the risk to fertility.

‘Hypomethylating’ chemotherapy drugs such as decitabine have shown great promise in the lab, particularly for the treatment of colorectal cancer. Are there any treatments currently being researched or in trial that you think are particularly encouraging?

As well as conventional chemotherapy agents such as 5-fluorouracil and capecitabine, and platinum-based drugs, there are existing antibody-based treatments (monoclonal antibodies) that deprive tumours of new blood vessels or block the cancer cells from reproducing, such as bevacizumab. Decitabine is a drug from the same family as capecitabine which has been used in other cancers including leukaemia, showing promise in colorectal cancer. Of the developments in colorectal cancer treatment, one of the most important is the genetic subtyping of tumours. In the future, this subtyping may help predict which tumours are the most aggressive, and which will be vulnerable or resistant to specific targeted treatment. This would mean that the right people get the right drugs, so that fewer people would suffer the side effects of treatment that are ineffective for them. Several cellular protein ‘targets’ have been identified, which is the first step before engineering drugs that act on those targets. One example of a protein that has been identified in tumour development and is now being targeted is STAT3, which can be involved not only in colorectal cancer, but also melanoma, as well as breast, ovarian, and prostate cancer (PrC).

What more do you think could be done to inform men of their PrC risk levels? Is routine screening the answer?

The opportunity for sharing information on social media has been a great asset for all areas of health, including PrC. Men and their families can now find a range of resources and support from medical professionals and peers easily, rapidly, cheaply, and without the embarrassment factor. Men are more aware of the risk of PrC than a generation ago, when it tended to be ‘hushed-up’. In terms of screening for PrC, there is a great deal of controversy. The problem with all screening programmes, whether for breast, bowel, prostate, or any other cancer, is that there may be over-diagnosis and over-treatment. This means that people without the disease may undergo unnecessary and unpleasant investigations, and those with a version of the disease that was indolent, or not at all aggressive, may end up having unnecessary invasive treatment. While there is evidence for the effectiveness of PrC screening using the prostate specific antigen blood test, screening all men will result in over-diagnosis. Over-treatment is becoming less of an issue, as the aggressiveness of the various grades of PrCs is now very well understood, and increasingly the low-risk cases of PrC are simply monitored. No-one should advocate for all men to be screened, as only relatively healthy men with at least 7 years of life expectancy will benefit from aggressive treatment of PrC due to its relatively slow progression. Men with no family history of PrC probably do not need screening until the age of 50, and in general those over the age of 68 will not benefit, but there is no universal agreement on screening guidelines. For more on the concept of screening, see this short video: https://www.youtube.com/watch?v=64ZciiSlDrk.

With more and more exciting discoveries in PrC research emerging, for example the discovery that PrC may be distributed into five types depending on genetic signatures, what do you think has been the most important development recently that will lead to new treatments for people with the condition?

Our increased understanding of PrC, and as a result the explosion in treatments for metastatic PrC has been a cancer success story over the past decade. We have seen treatments crop up in the areas of immunotherapy, novel androgen receptor targeted agents, systemic radiotherapy agents, new uses for existing chemotherapy drugs, new scanning techniques, and new surgical and radiation therapy options. As well as new research on treatments that are variations on existing drugs, there are agents that have shown efficacy against PrC cells in the laboratory that await clinical trials, including a modified pox virus, and antibodies that stimulate the immune system to destroy cancer cells, prevent tumours from growing a blood supply, or signal the cells to destroy themselves. All of these are exciting areas for development, but are some years away from clinical use.

Importantly, there are several studies underway with the intention of determining what the optimal order for providing the existing treatments is, in order to maximise benefits in symptom control and survival.

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