ADT not a PATCH on E2!
Amongst AnCan regular participants, we are honored to include Dr. Paul Schellhammer. Dr. Paul is a venerable, highly respected urologic oncologist – in simpler terminology, a cancer urologist! His more prestigious gigs included President of the American Urology Association; his less prestigious include being a member of our AnCan Brains Trust and frequent, highly valued contributor in the AnCan Hi Risk/Rec/Adv Group.
Dr. Schellhammer is an advanced prostate cancer peer, and has spent some 20+ years on Estradiol/E2. We are so grateful he agreed to provide a commentary on the watershed report published in the March 25th New England Journal of Medicine, that also appeared digitally this week, Transdermal Estradiol Patches in Locally Advanced Prostate Cancer, Ruth E. Langley FRCP et al.
Thank you Dr. Paul!
The recently reported PATCH trial has reintroduced estrogen as an effective agent in the treatment of advanced carcinoma of the prostate. A brief review of estrogen/prostate cancer history is appropriate.
The first drug used to treat prostate cancer was a synthetic estrogen called Diethylstilbestrol (DES). It was effective in lowering testosterone and controlling the cancer but caused dangerous life threatening blood clots. It was replaced in the 1980’s by Lupron and many similar LHRH agonists (LHRHa) which lowered testosterone without the blood clot side effect. (Ed: LHRHa include Lupron, Zoladex, Eligard, Trelstar)
Over 20 years ago Dr. Paul Abel ,a urologist in London, UK suggested that the blood clot issues associated with DES were due to oral ingestion and that estrogens would be safe for ADT if absorbed instead through the skin. This idea gave birth to the PATCH (prostate adenocarcinoma transcutaneous hormone) trial, which was subsequently incorporated into a larger trial called STAMPEDE as a large, multi-year large trial conducted across many sites in the UK.
The results of the PATCH/STAMPEDE trial were published in the New England journal of Medicine (https://doi.org/10.1056/NEJMoa2402606). Key findings are summarized as follows.
EFFICACY: Transdermal estradiol (tE2) ADT (Androgen Deprivation Therapy) suppresses testosterone and reduces PSA as well as LHRHa ADT drugs, but has fewer adverse effects and significantly lower costs.
SURVIVAL: tE2 ADT is non-inferior compared to LHRHa ADT in terms of 3-year Metastasis-Free Survival and 5-year Overall Survival rates.
TESTOSTERONE SUPPRESSION: tE2 ADT suppresses testosterone below the castrate threshold in 94% of men.
BONE HEALTH: tE2 ADT increases bone mineral density by 6% at 1 year, and reduces fracture rates by 50% at 5 and 10 years when compared to LHRHa ADT.
HOT FLASHES (VASOMOTOR SYMPTOMS): tE2 ADT significantly reduces hot flashes compared to LHRHa ADT.
tE2 controls cancer equally well as an LHRHa. Importantly, to the bone issue, it is not only bone protective, it is bone-building as demonstrated with bone density scans. It counters the bone mineral loss associated with both the normal male aging process and LHRHa ADT thereby reducing the morbidity and mortality of osteoporotic fracture.
The clinical impact of this bone protective benefit is considerable in the context of doublet therapy (LHRHa plus an Androgen Pathway Receptor Inhibitor) which is now considered standard of care when delivering ADT in most recurrent and advanced prostate cancer.
A recent SEER-Medicare study reported that the fracture rate at three years with doublet therapy, using standard LHRHa drugs, is 25% percent despite the addition of bone protective agents. In the recent report from the EMBARK trial, doublet combination of enzalutamide plus LHRHa improved disease control end points compared to LHRHa alone. Also reported was a greater adverse impact on quality of life. While doublet therapy with a LHRHa backbone is tougher on the cancer, it is also tougher on the patient.
There have been a number of pharmacologic strategies proposed to minimize the adverse impact of hot flashes, interrupted sleep, fatigue, weight gain associated with LHRHa, but they just add to the patients medication list (polypharmacy) and costs, and have their own set of side effects. ADT with tE2 avoids/eases these issues for most men.
The main adverse event associated with tE2 is nipple sensitivity and breast enlargement. The manner by which this is presented by physicians to patients will influence patients’ decision on ADT options. If the physician begins by describing tE2 as a form of treatment that uses a female hormone that causes big breasts, the discussion will likely end.
Instead, a reasonable discussion might acknowledge that both LHRH analogs and estradiol can cause some breast enlargement. Although more common with tE2, a review that my colleagues undertook for the Estradiol Initiative (see: https://estradiolinitiative.org/for-patients/gynecomastia-and-mastalgia-as-side-effects-of-supplemental-estradiol/) suggests that the amount of breast growth likely to be induced by tE2 is in the range of bra A cup size or less.
To minimize breast enlargement, a single dose of radiation can be delivered prior to beginning ADT. If enlargement and nipple sensitivity is an excessive bother, an outpatient surgical procedure can successfully address both enlargement and discomfort. Gynecomastia, the medical term for breast enlargement, is a cosmetic issue and quite distinct from the long-term adverse systemic effects on metabolic, cardiovascular, musculoskeletal and neurocognitive function that are associated with LHRHa ADT. This presents a trade-off worthy of transparent discussion, where patients are presented with both the risks and benefit of all options for ADT.
In addition, an under-appreciated and often overlooked issue regarding ADT toxicity is the impact of traditional ADT on the quality of life of the partners/carers of patients. Partners/carers often bear the emotional brunt of a ADT patients’ flagging disposition.
The presence of a certain level of estrogen in men is essential for normal health and function. However, traditional ADT by surgical or pharmacological castration deprives men of not just testosterone, but also estrogen. The problem of loss of estrogen can be avoided in a very cost-effective way simply by using tE2 for ADT and , thereby, address the increasing concerns regarding financial toxicity.
In writing this essay, I speak from personal experience. I have switched from ADT with LHRHa to tE2 on two occasions. The positive effect of tE2 was dramatic enough that I included it in an essay on ADT and quality of life: (https://bjuijournals.onlinelibrary.wiley.com/doi/full/10.1111/bju.13737)
In essence, my LHRHa to estradiol switch was accompanied by more energy, better sleep, a more positive overall outlook, and what I term as an “increased sexual awareness and appreciation“.
My hopes are that the NCCN guideline committee will include transdermal estradiol as an ADT lternative, that physicians will inform patients of the advantages of transdermal estradiol ADT and, for those patients having significant quality of life difficulties with traditional ADT, offer to switch to transdermal estradiol. Physicians will often be impressed as to how the patient and the patient’s wife and family members will gratefully respond .
One last observation: Medical oncologists, during training and in practice, administer toxic agents to very ill compromised patients. The adverse events are serious and sometimes fatal. These treatments span months – not years and decades. Against this background, ADT complaints are not urgent or immediately life-threatening and may fall to the background with a comment that ADT is generally “well tolerated“. In my opinion, this term “well tolerated“ finds validity only when it comes from a physician who is informed by a lived personal experience with a course of LHRH therapy.