Tower of Hanoi | Climax

Rationale for evidence-based Medicine 

(Fictional narrative by the doctor)

James Fleck, MD, PhD & João A de Andrade, MD

Anticancerweb 06 (03), 2019

Before making recommendations to a patient regarding diagnostic procedures or treatment options, physicians seek the medical literature in search of the latest knowledge. This is called “evidence-based medicine” and, as one can imagine, medical evidence has different levels of quality and strength. For example, well-designed randomized controlled clinical trials, where patients are prospectively and blindly assigned either active drug or a placebo and then followed for long periods of time are generally considered to have a very strong level of evidence. They often provide definitive evidence on whether a given treatment or drug is beneficial or not. On the other hand, single patient case reports are considered to have a much lower level of evidence. At times, physicians are left without any firm guidance given the rarity of a disease or lack of research that can inform their decisions. Fortunately, this is not the case with prostate cancer! 

It was late at night and I was researching the literature to develop my treatment recommendations for Theophilus. He would return to my office the next morning and I was anticipating many questions and a demand for evidence to back up my plan. I was relying on the latest guidelines published by international medical societies, such as the American Society of Clinical Oncology (ASCO), the American Society of Radiation Oncology (ASTRO) and the Society of Urologic Oncology (SUO). I also searched and reviewed the latest publications from the most respected oncology journals.  I wanted to give him the best and latest evidence-based recommendations, but I was already anticipating a potential new challenge. 

Theophilus arrived alone. 

Based on AJCC + UICC 8^th edition his prostate adenocarcinoma was clinically classified as T3bN0M0, Gleason 8 (4+4), with a PSA > 20. These features translated to a stage IIIB (out of four). Although Gleason 8 (4+4) or PSA > 20 indicated a high-risk for progressive or recurrent disease, the invasion of seminal vesicles put him in an even higher risk group. Invasion of the seminal vesicles was the main reason why surgery was not recommended. The urologist had called me earlier to share his concern that Theophilus had a high chance of incomplete prostate resection. Furthermore, even if we performed a radical prostatectomy, the need for additional radiation therapy could not be avoided.

With this background in mind, my recommendation was for treatment with a combination of external bean radiation therapy (EBRT) + androgen deprivation therapy (ADT). Even at  stage IIIB, this treatment was designed with the intent to cure, but he needed to be made aware of the expected complications. The main acute toxicities include urinary symptoms, abdominal cramping, rectal pain and increased urge to defecate. Most of them would be temporary, extending for only one or two months following the end of EBRT. I suggested an EBRT technique called image-guided radiation therapy (IGRT), which used a better-defined radiation field, leading to less toxicity.

Multiple randomized clinical trials have shown that patients with prostate cancer have better survival when EBRT is combined with ADT. Prostate cancer progression is related to the male sex hormone testosterone. ADT is a modality of treatment that effectively reduces the production of testosterone. Nowadays, ADT is mainly based on a drug called Goserelin, which is a gonadotropin releasing hormone (GnRH) agonist. Goserelin is given subcutaneously once a month, and leads to what is called “chemical orchiectomy”. In other words, if effectively reduces testosterone levels without the need for surgical removal of the testicles (orchiectomy). The drug causes a disruption in the hormonal feedback system by rapidly binding to GnRH receptor cells in the pituitary gland, thereby increasing luteinizing hormone (LH) secretion, and temporarily stimulating a higher production of testosterone (a phenomenon called flare). Two or three weeks later, there will be a receptor downregulation, reducing testosterone blood levels that are equivalent to those seen in patients who had their testicles removed surgically.

Theophilus had read about “prostate conservation treatments” and knew the benefits and potential pitfalls related to EBRT + ADT. He followed my explanation attentively, nodding his head from time to time. He agreed that it seemed the best option and was willing to accept most of the expected treatment-related complications. However, he was very concerned about the possibility of erectile disfunction.

Most patients undergoing EBRT+ADT develop loss of libido and sexual dysfunction from the prolonged use of ADT. His locally advanced disease called for combination treatment and I would recommend ADT for a period of three years. After discontinuation of ADT, erectile function would be expected to slowly recover. I suggested him to discuss this issue with his wife and I made myself available to further discuss the matter with them during our next appointment.

I reassured him that he would be closely followed throughout the treatment. Although his main concern was related to sexual disfunction, I wanted to make him aware of other potential late complications from ADT. Sarcopenia (loss of muscle mass) and osteoporosis (loss of bone mass) could be mitigated through physical activity. If we observed osteoporosis, we would use a drug called desonumab which inhibits bone loss and reduces the risk of fractures.  Sometimes ADT is associated with an increasing in body fat so he would need to follow a healthy diet to avoid gaining too much weight. Also, I reassured him that I would routinely check him for any other metabolic and cardiovascular drug-induced toxicity.

This was an atypical appointment!

Theophilus remained unusually quiet. It was obvious that, as I explained the benefits and risks associated with the treatment, he was reflecting on all the changes and challenges he was about to face.

Expressing mixed feelings about the proposed plan, he asked for a few days to think about…

*       Attention: The story 2 will be published sequentially from the PLOT 1 to the PLOT 6, however it will appear backwards. So, you will always see the most recent publication. Just browse in numbered pages located at the bottom of the homepage and start to read the story 2 from the beginning. 

To be continued in PLOT 5 (falling action): Mature love

© Copyright 2019 Anticancerweb

 James Fleck, MD, PhD: Full Professor of Clinical Oncology at the Federal University of Rio Grande do Sul, RS, Brazil 2019

Joao A. de Andrade, MD: Professor of Medicine and Chief Medical Officer, Vanderbilt Lung Institute, Vanderbilt University Medical Center, Nashville, TN – USA 2019 (Associate Editor)