|Year : 2022 | Volume
| Issue : 3 | Page : 268-271
Prevalence of skeletal-related events in hormone-naive prostate cancer in a low resource setting
Fredrick Obiefuna Ugwumba1, Ikenna Ifeanyi Nnabugwu1, Agharighom David Okoh1, Kevin Ndubuisi Echetabu1, Okechukwu Onwuasoigwe2, Ekeoma Okey Nwosu2
1 Department of Surgery, Urology Unit, College of Medicine, University of Nigeria Enugu Campus, Enugu, Nigeria
2 Department of Surgery, Orthopaedic Surgery Unit, College of Medicine, University of Nigeria Enugu Campus, Enugu, Nigeria
|Date of Submission||18-Mar-2022|
|Date of Decision||06-Jun-2022|
|Date of Acceptance||30-Jun-2022|
|Date of Web Publication||22-Jul-2022|
Ikenna Ifeanyi Nnabugwu
Department of Surgery, Urology Unit, College of Medicine, University of Nigeria Enugu Campus, Enugu
Source of Support: None, Conflict of Interest: None
Background: Presentation with symptoms of advanced prostate cancer is prevalent in developing societies. The objective of this study was to determine the rate of and factors associated with skeletal-related events (SREs) at presentation with hormone-naïve prostate cancer. Methods: Records of 331 consecutive prostate cancer patients from January 2009 to April 2018 were reviewed. The prevalence of SRE at the presentation was determined. In addition, the relationships between SRE and age of patient, duration of clinical features, serum total prostate-specific antigen (tPSA) and biopsy Gleason score (GS) at presentation were evaluated. Analyses were done with IBM SPSS® version 25. Results: Mean age was 69.8 ± 8.0 years. While 43.8% of patients had lower urinary tract symptoms (LUTS) only, 51.4% had LUTS and other features of disease progression. Only 2.1% of the cases were confirmed from screen detection of elevated serum tPSA. SREs were observed in 11.8% at first presentations with hormone-naïve prostate cancer. Symptom duration (odds ratio [OR] 0.94; 95% confidence interval [CI] 0.90–0.99; P = 0.02), anaemia that could not be attributed to gross haematuria or external blood loss (OR 9.6; 95% CI 3.12–29.52; P < 0.001) and transrectal biopsy GS (OR 1.61; 95% CI 1.17–2.22; P = 0.003 ) were significantly associated with SREs at presentation with hormone-naïve prostate cancer. Conclusions: Evidence exists that patients who present with SREs from more aggressive prostate cancers may have had more rapid symptom progression, but not a longer delay before presentation.
Keywords: Gleason score, initial presentation, prostate cancer, skeletal-related events, symptom duration
|How to cite this article:|
Ugwumba FO, Nnabugwu II, Okoh AD, Echetabu KN, Onwuasoigwe O, Nwosu EO. Prevalence of skeletal-related events in hormone-naive prostate cancer in a low resource setting. Niger Postgrad Med J 2022;29:268-71
|How to cite this URL:|
Ugwumba FO, Nnabugwu II, Okoh AD, Echetabu KN, Onwuasoigwe O, Nwosu EO. Prevalence of skeletal-related events in hormone-naive prostate cancer in a low resource setting. Niger Postgrad Med J [serial online] 2022 [cited 2022 Aug 10];29:268-71. Available from: https://www.npmj.org/text.asp?2022/29/3/268/351724
| Introduction|| |
Prostate cancer is the most common cancer in men both globally and in Nigeria.,, Adenocarcinoma of the prostate is the most common histologic type and the second most lethal cancer of the urinary tract after renal cancer. Screening-detected prostate cancer tends to be early disease while prostate cancer diagnosed as a result of symptoms tends to be late and advanced disease. In many resource-poor settings, presentation with advanced, but hormone-naïve prostate cancer is prevalent.,
Skeletal-related events (SREs) make up a group of clinical features seen in metastatic cancers that increase the burden of health care consequent upon the urgent need for some resuscitating and stabilizing interventions. Other late features of advanced disease at presentation that increase the burden of initial and continuing health care include severe anaemia, obstructive nephropathy and recalcitrant haematuria., According to GLOBOCAN data and reports from other studies, there exists a high burden of health care for prostate cancer in Nigeria and some other developing countries of black Africa due to late first presentation with life-threatening clinical features of high-risk aggressive disease.,,
Conventionally, studies from more developed settings report SREs mostly in the context of castration-resistant prostate cancer., On the other hand, in the less developed low-resource settings, SREs and other clinical features of advanced prostate cancer are seen also at initial presentation due to lateness in seeking health care. It is the main aim of this study to determine the proportion of SREs among men presenting first time with hormone-naïve prostate cancer in Enugu, an urban area in South-east Nigeria. The study will also assess disease-related factors that are associated with these SREs. This knowledge acquired from this study will assist in determining the contribution of SREs to the clinical burden of initial care in our resource-poor setting.
| Methods|| |
Following ethical approval from the Health Research Ethics Committee of the University of Nigeria Teaching Hospital (NHREC/05/012008B-FWA00002458-1RB0002323 issued February 10, 2020), the medical records of consecutive patients managed for histologically confirmed adenocarcinoma of the prostate from January 2009 to April 2018 were retrieved for the analysis. These patients were managed in line with established urology unit protocol. Transabdominal ultrasonography and transrectal ultrasonography (TRUS) were done to assess the status of the prostate and other abdominal organs. Full blood count, serum total prostate-specific antigen (tPSA) assay and serum electrolytes, urea and creatinine were also done. Plain radiographs were done for suspected or obvious bone lesions, abdominal computed tomography (CT) scan was done for suspected organ-confined disease, spinal CT scan was done for suspected spinal metastasis while spinal magnetic resonance imaging (MRI) was done instead in cases of suspected spinal cord involvement. Tissue for histology confirmation and Gleason Score (GS) were obtained by transrectal prostate biopsy. Each patient was managed according to stage of the disease and the problems at presentation. All patients with metastatic disease were offered androgen deprivation therapy (ADT) as first line therapy. External-beam radiotherapy was offered to those presenting with paraparesis or paraplegia who do not show objective clinical response within 4 weeks of ADT. The records were retrieved in the months of March and April 2020.
From the medical records, age of patients, presenting clinical features with their duration, features of the prostate on digital rectal examination and on TRUS scan, and serum tPSA values were obtained. In addition, findings from plain radiographs of bones, CT scans of abdomen and spine and MRI of spine as applicable were retrieved. A SRE was defined as the presence of pathologic fracture due to bone metastasis, paraparesis or paraplegia from spinal metastasis, or a necessity for radiation or surgery to bone to obviate same.
Descriptive statistics were obtained for each of the variables. The relationships between SREs at presentation and other variables independently were studied using univariate analyses. In addition, multivariate analysis was used to determine the contributions of age of patient, symptom duration, haematuria, anaemia, serum tPSA and prostate biopsy GS to presentation with SREs. All analyses were done using SPSS version 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY, USA: IBM Corp.).
| Results|| |
Of a total of 342 consecutive cases of hormone-naïve prostate cancer within the study period, 331 have enough information to be included for the analysis. About 3.9% of the cases presented with organ-confined disease by abdominal CT evaluation while about 11.8% presented with SREs by plain radiography or CT assessment. They were all Nigerian men between the ages of 51 years and 90 years. [Table 1] shows the descriptive statistics of the variables of interest.
There were 40 (12.0%) men that presented with anaemia, among which are 18 (5.4%) that had no associated history of gross haematuria or external blood loss. With regard to SREs, 7 (2.1%) had pathological fracture of a limb bone, 19 (5.7%) had paraparesis and 13 (3.9%) had paraplegia. The median duration of symptoms was 7 months (IQR 3–24 months) for all patients, but 4 months (IQR 3–6 months) for those presenting with these SREs. There was also a tendency for those with shorter duration of symptoms at presentation to have higher grade tumours at biopsy (γ-0.033; P = 0.57). In other univariate analyses, these SREs were reported more frequently among men who presented with higher grade tumours (χ2 12.45; df 4; P = 0.014) and among the men with anaemia in the absence of prior history of gross haematuria or any external blood loss (χ2 26.748; df 1; P < 0.001). There is no evidence that these SREs were more frequently reported among men presenting with higher serum tPSA (χ2 3.252; df 3; P = 0.354).
In [Table 2], the proportions of patients that demonstrated remission of paraparesis, paraplegia and bone pain with ADT and radiotherapy are shown. In the case of paraparesis or paraplegia, remission is the regaining of power in the lower limbs enough to ambulate with minimal or no support, while for bone pain, remission is reduced need for analgesics.
|Table 2: Proportion of patients that showed at 8 weeks post-androgen deprivation therapy remission of skeletal-related events and other bone pains|
Click here to view
The binary logistic regression model created is significant statistically (χ2 40.588; df 8; P < 0.001) and explains 24.5% (Nagelkerke R2) of the variance in presentation with SRE. The model correctly classifies 88.5% of cases that presented with SRE with a sensitivity of 14.3%, specificity of 98.1%, a positive predictive value of 0.5% and negative predictive value of 89.8%. [Table 3] shows the output from the analysis.
|Table 3: Output of binary logistic regression analysis of variables that influence the presence of any skeletal-related event|
Click here to view
| Discussion|| |
From this review, presentation with symptoms is the norm [Table 1] as only 2.1% of the cancer diagnoses are from elevated serum tPSA only. It appears therefore, that many men continue to carry on with life up until a bothersome symptom forces them to seek medical care. The implication of this is that late presentation in advanced stages of the disease remains prevalent. This is similar to the work from South-west Nigeria and from other sub-Saharan African countries. Symptoms encountered at first presentations are lower urinary tract symptoms (LUTS) of varying severity as well as various symptoms of locally-advanced and metastatic diseases [Table 1].
Presentation with LUTS with or without other clinical features is prevalent (95.2%) from this study. In more than half of the time (54.1%), the patient presents with other clinical features besides LUTS, that obviously impact negatively on the patient's quality of life and increase the burden of healthcare., In particular, a SREs is present in approximately 1 of every 10 patients at first presentation. Similarly, the work by Badmus et al. from South-west Nigeria reports that about 22% of the patients in the study presented at the first instance with inability to walk. SREs are known to increase length of hospital stay and number of hospital visits., In addition, SREs are known to require active input from many more disciplines of care. The study by Body et al. shows a 50%–150% increase in mean inpatient stay per SREs. All such first presentations with SRE require immediate hospital admission for resuscitation and stabilization. To add to the clinical burden, further assessments of all these patients to confirm diagnosis and to stage the disease are done as inpatients.
In the developed countries, SREs in prostate cancer are usually seen during follow-up in patients with castrate-resistant prostate cancer and second-line therapeutic strategies and Radium 223 therapy are indicated.,,,, In the setting of SREs in hormone-naïve prostate cancer, first-line androgen deprivation strategies can be instituted, and they can produce remission of symptoms in a reasonable proportion of patients [Table 2].
In relation to other patients, there is some evidence [P = 0.02; [Table 3]] that those presenting with these SREs may not have endured earlier symptoms of prostate cancer for a longer duration before coming down with SRE. It is probable that these highly aggressive cancers, progressing rather rapidly, reach advanced stages within shorter periods making presentation in advanced stages almost inevitable. The review by Schiewer and Knudsen summarizes that in prostate cancer, alterations in DNA repair genes such as Retinoblastoma 1, P53, TP53, breast cancer gene (BRCA) 1 and BRCA 2 genes increase the risk of the malignancy being more aggressive, and of the patient presenting with metastasis at diagnosis. It could be deduced that these SREs in men with hormone-naïve prostate cancer are associated with high grade, poorly differentiated prostate cancer as well as with shorter duration of preceding symptoms.
Similarly, there is higher odds (odds ratio [OR] 9.6; 95% confidence interval [CI] 3.12–29.52; P < 0.001) of SREs among those presenting with anaemia, especially where the anaemia is not attributable to gross haematuria or any other external blood loss, but can only be explained by possible bone marrow infiltration or suppression by highly aggressive malignant disease. Metastatic bone disease in terms of marrow infiltration or cortical invasion is seen in this review to be closely associated.
Being a retrospective study, the data retrieved from records were not obtained from the primary sources through controlled circumstances. Because of the challenge with determining severity of pain in bone metastatic sites, bone pain which may not qualify to be classed as an SRE could not be determined. Hence, bone pain without pathologic fracture, paraparesis or paraplegia was not included in SRE group.
| Conclusions|| |
In all, symptomatic presentations, mostly in advanced stages, remain prevalent in this low-income setting. The clinical features of advanced metastatic diseases such as obstructive nephropathy, anaemia and SREs are frequently observed at first presentation with hormone-naïve prostate cancer. There is strong evidence that those presenting with these SREs have higher grade, more aggressive prostate cancers. It is also probable that symptomatic prostate cancers culminating in an SRE may have progressed more rapidly in the men that came down with these SREs and not necessarily that these men delayed longer with their earlier symptoms. Institution of ADT leads to reversal of symptom progression in a good number of these patients.
The authors are grateful to Chuma Onyejizu, Uchechukwu Ogbobe, Nonso Ozoalor, Augustine Okonkwo and Paschal Maduabuchi for their roles in data collection.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, Alizadeh-Navaei R, et al.
Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA Oncol 2018;4:1553-68.
Ekanem IO, Parkin DM. Five year cancer incidence in Calabar, Nigeria (2009-2013). Cancer Epidemiol 2016;42:167-72.
Jedy-Agba E, Curado MP, Ogunbiyi O, Oga E, Fabowale T, Igbinoba F, et al.
Cancer incidence in Nigeria: A report from population-based cancer registries. Cancer Epidemiol 2012;36:e271-8.
Adewumi AO, Anthonia SC, Alabi AS, Amina FO, Kingsley KK. Pattern of prostate cancer among a Nigerian population: A study in a single tertiary care centre. Niger J Med 2016;25:70-6. [Full text]
Pang C, Guan Y, Li H, Chen W, Zhu G. Urologic cancer in China. Jpn J Clin Oncol 2016;46:497-501.
Kirakoya B, Hounnasso PP, Pare AK, Mustapha AB, Zango B. Clinico-pathological features of prostate cancer at the University Hospital Yalgado Ouedraogo, Ouagadougou, Burkina Faso. J West Afr Coll Surg 2014;4:70-81.
Ibrahim T, Mercatali L, Amadori D. A new emergency in oncology: Bone metastases in breast cancer patients (Review). Oncol Lett 2013;6:306-10.
Dewar M, Kaestner L, Zikhali Q, Jehle K, Sinha S, Lazarus J. Investigating racial differences in clinical and pathological features of prostate cancer in South African men. S Afr J Surg 2018;56:54-8.
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al
. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon: International Agency for Research on Cancer; 2013.
Okoye JO. High mortality risk of prostate cancer patients in Asia and West Africa: A systematic review. Avicenna J Med 2020;10:93-101. [Full text]
So A, Chin J, Fleshner N, Saad F. Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice. Can Urol Assoc J 2012;6:465-70.
Fizazi K, Scher HI, Miller K, Basch E, Sternberg CN, Cella D, et al.
Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: Results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 2014;15:1147-56.
Badmus TA, Adesunkanmi AR, Yusuf BM, Oseni GO, Eziyi AK, Bakare TI, et al.
Burden of prostate cancer in southwestern Nigeria. Urology 2010;76:412-6.
Cassell A, Yunusa B, Jalloh M, Ndoye M, Mbodji MM, Diallo A, et al.
Management of advanced and metastatic prostate cancer: A need for a Sub-Saharan guideline. J Oncol 2019;2019:1785428.
Yong C, Onukwugha E, Mullins CD. Clinical and economic burden of bone metastasis and skeletal-related events in prostate cancer. Curr Opin Oncol 2014;26:274-83.
Broder MS, Gutierrez B, Cherepanov D, Linhares Y. Burden of skeletal-related events in prostate cancer: Unmet need in pain improvement. Support Care Cancer 2015;23:237-47.
Body JJ, Pereira J, Sleeboom H, Maniadakis N, Terpos E, Acklin YP, et al.
Health resource utilization associated with skeletal-related events: Results from a retrospective European study. Eur J Health Econ 2016;17:711-21.
Mulders PF, Abrahamsson PA, Bukowski RM. Burden of metastatic bone disease from genitourinary malignancies. Expert Rev Anticancer Ther 2010;10:1721-33.
Rizzini EL, Dionisi V, Ghedini P, Morganti AG, Fanti S, Monari F. Clinical aspects of mCRPC management in patients treated with radium-223. Sci Rep 2020;10:6681.
Brito AE, Etchebehere E. Radium-223 as an approved modality for treatment of bone metastases. Semin Nucl Med 2020;50:177-92.
Schiewer MJ, Knudsen KE. Basic science and molecular genetics of prostate cancer aggressiveness. Urol Clin North Am 2021;48:339-47.
Kucukzeybek BB, Calli AO, Kucukzeybek Y, Bener S, Dere Y, Dirican A, et al.
The prognostic significance of bone marrow metastases: Evaluation of 58 cases. Indian J Pathol Microbiol 2014;57:396-9.
] [Full text]
[Table 1], [Table 2], [Table 3]