Genitourinary Cancer – 11
(All the articles published in past are available at www.shyamhemoncclinic.com/blog/)
Question: Thank you Chiragbhai for several interesting points about treatment of Metastatic prostate cancer. 1. Metastatic or stage 4 prostate cancer is one of the easiest to treat, with excellent initial results in majority. Androgen hormone suppression using GnRH analogues or removing source of hormones i.e. testes is the first treatment. 2. This treatment is known as ADT – Androgen Deprivation Therapy. It is generally well tolerated. Some patients develop symptoms similar to that seen with menopause in women.
You mentioned that after about 1.5-2 years, cancer cells develop hormone independence i.e. become resistant and start growing again. What options do we have at that time? And how is the prognosis?
Answer: This is a comparatively difficult time, as the options now are not as easy as ADT. This stage known as HRPC – hormone refractory prostate cancer, has variable course however. Some patients have slowly rising PSA without symptoms or visceral involvement. Some have much more marked symptoms, visceral involvement and large rise in PSA. And others have intermediate aggressiveness.
Traditionally, only options in this stage were either additional hormone therapy (like bicalutide) or chemotherapy docetaxel (or mitoxantrone) or supportive care. A number of these patients are old and frail, and cannot tolerate chemotherapy well. Patients with slow rise in disease may benefit from bicalutide or flutamide, which blocks binding of androgen hormone to androgen receptor on surface of cancer cells. This remaining androgen hormone comes mainly from adrenal gland.
ONE IMPORTANT ROLE for these antiandrogen agents worth mentioning is in combination with initial ADT. They should be combined with ADT for at least first 1-3 months to prevent a flare of disease, more importantly in patients with severe symptoms or cord compression. With GnRH analogues, there is a risk of disease flare in some patients. This initial hormone surge is blocked by bicalcutide or flutamide. Some physicians give bicalutamide for long term till progression, however that is controversial, and most likely there is no additional benefit beyond initial role.
Efficacy of oral antiandrogens like bicalcutide in HRPC is however low and even when it works, lasts only for few weeks to months. It remains an option however for slow rising disease. More aggressive disease on the other hand requires chemotherapy. Mitoxantrone is fairly easy to tolerate but did not improve survival. Docetaxel was the first chemotherapy drug to show clear improvement in overall survival, in 2004, in well designed randomized clinical trials (SWOG 9916, TAX 327) and became the standard of care for several years. Median survival was 18 months. Drug however is frequently not tolerable in elderly population. Especially at full 3 weekly dose, several oncologists have experienced significant side effects and intolerance. One modification we frequently use is dividing the dose of three weekly regimen in two weeks. For example, giving 30-35 mg/m2 dose every week for two weeks, followed by one week off, instead of a 60-75 mg/m2 every 3 weeks. This ensures safer, more tolerable administration. If patient tolerates drug very well on weekly regimen, we may switch to 3 weekly from 2nd or 3rd cycle. This is exactly what we did recently for a 75 year old gentleman, uncle of a senior doctor in city. Thus all elderly are not same, and a small but significant minority can tolerate it well and achieve good clinical benefit.
Que: What about the new options in this stage?
Ans: Two new options are now widely available in this stage. These are also hormone therapies in a sense, as they work at removing hormone resistance at several levels including nuclear level. Both are oral, and work slowly in general. They are good options for slowly rising PSA or with low symptom burden. MOST IMPORTANTLY, both have shown improvement in overall survival, after failure of docetaxel AND in patients who have not received chemotherapy yet.
First approved option Abiraterone is more widely used in India, mainly due to its first approval and due to many generics available with large cost reductions. It is generally safe and well tolerated. However one needs to be careful with fluid retention, hypertension, lowering of serum potassium levels. Second option is Enzalutamide. Also well tolerated. Few concerns are its seizure potential, tendency for falls.
Thus both options can be chosen based on patient’s existing comorbidities. Abiraterone has be given with low dose prednisolone, to avoid adrenal insufficiency. Not required however with Enzalutamide.
August 15th 2018.
Dr. Chirag A. Shah; M.D. Oncology/Hematology (USA), 079 26754001. Diplomate American Board of Oncology and Hematology. Ahmedabad. firstname.lastname@example.org