Three weeks ago, Minerva drew attention to the case of a 64-year old man presenting with an unusual cervicofacial abnormality subsequently diagnosed as actinomycosis(1). Such uncommon presentations often occur in patients who have, and continue to suffer, debilitating conditions (e.g. diabetes, immunosuppression, malnutrition, cancer) which progress over long periods of time. As a consequence, vulnerabilities are acquired that predispose to frailty and thereby enhance the risk of rare or infective disease developing. This man should be considered frail; and the report from Minerva implies periodontal disease to be the primary pathology pre-disposing him to actinomycosis. However, Minerva then reveals this man to also be suffering from metastatic prostate cancer (PC). Despite this, no mention of PC treatment appears in her report although, with proven metastases, he would very likely be receiving contemporary androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone agonist (LHRHa), causing a profound suppression of both testosterone (and estradiol – E2) to castrate levels and exacerbating frailty still further. ADT however has itself become increasingly recognized as responsible for serious adverse events, commonly including osteoporosis (with fractures), cognitive impairment, type 2 diabetes, hot flushes, cardiovascular complications and increased thromboembolic risk(2). Importantly, especially in this case, an association between ADT, LHRHa and periodontal disease has previously been published (2007), reporting the prevalence of periodontal disease to be 80% in men on ADT compared to 4% in those not on ADT(3). Awareness of common adverse events with ADT is generally lacking, poorly communicated and much contested amongst clinicians(4). Some less well known toxicities may be increasing and becoming more important, emphasizing even more the need for clinicians to possess up to date knowledge enabling them to engage patients fully when there may be a need for ADT treatment. It is essential patients are adequately counseled about the benefits and risks of ADT. In its 9th year since publication, this paper(3) has been cited on only 6 occasions whilst no mention of these relationships appears in Minervas’ report.
The increasing importance of appreciating the risks associated with ADT is further highlighted by a short report in the BMJ 2 weeks ago(5) . This summarized details of a brief publication in JAMA (Journal of the American Medical Association) concerning a clinical trial comparing long-term outcomes (median follow-up 16.6 years) in men with high risk local PC randomized to receive either radiotherapy alone vs men receiving radiotherapy combined with 6 months ADT, the latter intervention being standard of care. Survival was similar for men having radiotherapy alone and those randomized to combination therapy. However, amongst men with pre-existing moderate or severe comorbidity and receiving radiotherapy alone, overall survival was significantly better without ADT than with those having the radiotherapy/ADT (6). Thus reflecting the importance of careful selection of patients to receive ADT.
Further studies are required to expand this important knowledge base, continuing to explore issues such as those described and leading to better defined criteria which will enable therapeutic interventions that are more selective and targeted, hastening the time when choice and personalized medicine comes of age. The ongoing Phase III PATCH clinical trial(7), in which ADT is achieved by either transdermal estradiol patches or contemporary LHRHa has shown in pilot data that whilst both therapies deliver castrate levels of testosterone, serum estradiol levels are maintained in the patch arm but not the LHRHa arm, presumably a consequence of exogenous E2 replacing lost endogenous E2 in the patch arm. As such, PATCH is an example of the kind of study which seemingly, through repurposing, should enable some men to experience less, and others perhaps even avoid completely, the ‘menopausal’ type of E2 related adverse events that may otherwise occur with LHRHa. Such trials highlight the importance of continuing efforts to include collections of data that address co-morbidities associated with current gold standard therapy of advanced prostate cancer, aiming to ensure these issues are included and not missed, forgotten or ignored.
2. Ockrim J, El-Nasir Lalani, Abel P. Therapy Insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy. Nat Clin Prac Oncol 2006;3(10):552.
3. Famili P, Cauley JA, Greenspan SL. The Effect of Androgen Deprivation Therapy on Periodontal Disease in Men With Prostate Cancer. J Urol 2007;177(3):921-4.
4. Tran S, Walker LM, Wassersug RJ, Matthew AG, McLeod DL, Robinson JW. What do Canadian uro-oncologists believe patients should know about androgen deprivation therapy?. J Oncol Pharm Pract 2014; June 01;20(3):199-209
5. Wise, J. Androgen deprivation therapy should be used with caution in some prostate cancer cases, study warns. BMJ 2015;351:h5043.
6. D’Amico AV, Chen M, Renshaw A, Loffredo M,Kantoff PW. Long-term follow-up of a randomized trial of radiation with or without androgen deprivation therapy for localized prostate cancer. JAMA 2015; September 22;314(12):1291-3.
7. Langley RE, Cafferty FH, Alhasso AA, Rosen SD, Sundaram SK, Freeman SC, et al. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). The Lancet Oncol 2013; 4;14(4):306-16.
Competing interests:
No competing interests
08 November 2015
Hannah Wilson
Student
Molly Stewart, Matthew Arnold, Paul Abel
Imperial College London
Department of Surgery and Oncology, Charing Cross Hospital, W6 8RF
Rapid Response:
Re: Uncommon cervicofacial lesions
Three weeks ago, Minerva drew attention to the case of a 64-year old man presenting with an unusual cervicofacial abnormality subsequently diagnosed as actinomycosis(1). Such uncommon presentations often occur in patients who have, and continue to suffer, debilitating conditions (e.g. diabetes, immunosuppression, malnutrition, cancer) which progress over long periods of time. As a consequence, vulnerabilities are acquired that predispose to frailty and thereby enhance the risk of rare or infective disease developing. This man should be considered frail; and the report from Minerva implies periodontal disease to be the primary pathology pre-disposing him to actinomycosis. However, Minerva then reveals this man to also be suffering from metastatic prostate cancer (PC). Despite this, no mention of PC treatment appears in her report although, with proven metastases, he would very likely be receiving contemporary androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone agonist (LHRHa), causing a profound suppression of both testosterone (and estradiol – E2) to castrate levels and exacerbating frailty still further. ADT however has itself become increasingly recognized as responsible for serious adverse events, commonly including osteoporosis (with fractures), cognitive impairment, type 2 diabetes, hot flushes, cardiovascular complications and increased thromboembolic risk(2). Importantly, especially in this case, an association between ADT, LHRHa and periodontal disease has previously been published (2007), reporting the prevalence of periodontal disease to be 80% in men on ADT compared to 4% in those not on ADT(3). Awareness of common adverse events with ADT is generally lacking, poorly communicated and much contested amongst clinicians(4). Some less well known toxicities may be increasing and becoming more important, emphasizing even more the need for clinicians to possess up to date knowledge enabling them to engage patients fully when there may be a need for ADT treatment. It is essential patients are adequately counseled about the benefits and risks of ADT. In its 9th year since publication, this paper(3) has been cited on only 6 occasions whilst no mention of these relationships appears in Minervas’ report.
The increasing importance of appreciating the risks associated with ADT is further highlighted by a short report in the BMJ 2 weeks ago(5) . This summarized details of a brief publication in JAMA (Journal of the American Medical Association) concerning a clinical trial comparing long-term outcomes (median follow-up 16.6 years) in men with high risk local PC randomized to receive either radiotherapy alone vs men receiving radiotherapy combined with 6 months ADT, the latter intervention being standard of care. Survival was similar for men having radiotherapy alone and those randomized to combination therapy. However, amongst men with pre-existing moderate or severe comorbidity and receiving radiotherapy alone, overall survival was significantly better without ADT than with those having the radiotherapy/ADT (6). Thus reflecting the importance of careful selection of patients to receive ADT.
Further studies are required to expand this important knowledge base, continuing to explore issues such as those described and leading to better defined criteria which will enable therapeutic interventions that are more selective and targeted, hastening the time when choice and personalized medicine comes of age. The ongoing Phase III PATCH clinical trial(7), in which ADT is achieved by either transdermal estradiol patches or contemporary LHRHa has shown in pilot data that whilst both therapies deliver castrate levels of testosterone, serum estradiol levels are maintained in the patch arm but not the LHRHa arm, presumably a consequence of exogenous E2 replacing lost endogenous E2 in the patch arm. As such, PATCH is an example of the kind of study which seemingly, through repurposing, should enable some men to experience less, and others perhaps even avoid completely, the ‘menopausal’ type of E2 related adverse events that may otherwise occur with LHRHa. Such trials highlight the importance of continuing efforts to include collections of data that address co-morbidities associated with current gold standard therapy of advanced prostate cancer, aiming to ensure these issues are included and not missed, forgotten or ignored.
1. Pérez-Belmonte LM, Herrero-Lifona L, Laín-Guelbenzu JM. Uncommon cervicofacial lesions. BMJ 2015;351:h4547.
2. Ockrim J, El-Nasir Lalani, Abel P. Therapy Insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy. Nat Clin Prac Oncol 2006;3(10):552.
3. Famili P, Cauley JA, Greenspan SL. The Effect of Androgen Deprivation Therapy on Periodontal Disease in Men With Prostate Cancer. J Urol 2007;177(3):921-4.
4. Tran S, Walker LM, Wassersug RJ, Matthew AG, McLeod DL, Robinson JW. What do Canadian uro-oncologists believe patients should know about androgen deprivation therapy?. J Oncol Pharm Pract 2014; June 01;20(3):199-209
5. Wise, J. Androgen deprivation therapy should be used with caution in some prostate cancer cases, study warns. BMJ 2015;351:h5043.
6. D’Amico AV, Chen M, Renshaw A, Loffredo M,Kantoff PW. Long-term follow-up of a randomized trial of radiation with or without androgen deprivation therapy for localized prostate cancer. JAMA 2015; September 22;314(12):1291-3.
7. Langley RE, Cafferty FH, Alhasso AA, Rosen SD, Sundaram SK, Freeman SC, et al. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). The Lancet Oncol 2013; 4;14(4):306-16.
Competing interests: No competing interests