Treatment Results and Side Effects for Men With Localized Prostate Cancer in Low- and Middle-Income Countries

Table of Contents

• Key Points
• Background: Why This Research Matters
• How the Research Was Conducted
• What Studies Were Included
• Follow-Up Time and How Side Effects Were Measured
• Tools Used to Measure Side Effects
• Results After External Beam Radiation Therapy (EBRT)
• Results After Brachytherapy
• Results After Radical Prostatectomy
• Survival and Cancer Control Outcomes
• What These Findings Mean for Patients
• Limitations of the Study
• Recommendations for Patients and Health Systems
• Frequently Asked Questions
• Source Information

Key Points

• A review of 24 studies with 2,820 men in low- and middle-income countries examined side effects and outcomes after treatment for localized prostate cancer.
• After 3D-CRT, the most common side effects were mild: acute skin (46%), acute urinary (29%), acute bowel (24%), and late bowel (18%).
• Serious grade 3 urinary and bowel side effects after 3D-CRT were below 3%, and no grade 4 toxicities were reported.
• Five-year overall survival was 87% after 3D-CRT and 96% after combined brachytherapy plus external beam radiation therapy.
• The review excluded non-English publications, had average follow-up under 5 years, and found high variation between studies for many pooled results.

Background: Why This Research Matters

Prostate cancer is a growing health problem worldwide. Most new cases and most prostate cancer deaths now happen in low- and middle-income countries (LMICs). In 2020, there were 650,195 new prostate cancer cases in LMICs, and 237,032 men died from the disease.

The number of men diagnosed with prostate cancer worldwide is expected to double. It is projected to rise from 1.4 million in 2020 to 2.9 million by 2040. LMICs are expected to record the highest number of cases.

In most LMICs, prostate cancer is often not detected early or is diagnosed at advanced stages. Several barriers explain this pattern:

• Lack of awareness about the disease
• Lack of targeted screening programs
• Limited access to pathology services
• Poor follow-up data

Treatment options for localized prostate cancer in most LMICs include radical retropubic prostatectomy, which is surgical removal of the prostate. Options also include external beam radiation therapy (EBRT), which uses radiation from outside the body. Brachytherapy places radioactive seeds inside the prostate. Hormone therapy is another option. These treatments are used alone or in combination.

Radiation therapy is critical for both curative (aiming to cure) and palliative (relieving symptoms) care. Most LMICs have switched from 2-dimensional radiation therapy to 3-dimensional conformal radiation therapy (3D-CRT). Some centers also use high-precision techniques such as intensity modulated radiation therapy (IMRT), volumetric arch therapy, and stereotactic body radiation therapy (SBRT). Even though high dose-rate brachytherapy is available, low dose-rate brachytherapy is most commonly used.

Doctors consider many cancer-related outcomes when planning prostate cancer treatment. These outcomes include overall survival, metastasis (cancer spread), biochemical failure (a rise in prostate-specific antigen, or PSA, that suggests the cancer may be returning), and prostate cancer-specific death. Side effects in the gastrointestinal (bowel), genitourinary (urinary and sexual), and skin systems are equally important because of the location of the prostate.

Earlier systematic reviews have studied outcomes and side effects of localized prostate cancer treatments. However, those reviews did not separate data from high-income countries from data from LMICs. This made it difficult to make policy decisions for LMICs. One systematic review that focused on Africa alone suggested that men with localized prostate cancer survive longer. That finding was not extensively explored. The review lacked a meta-analysis and did not stratify outcomes by treatment. This systematic review and meta-analysis aimed to determine the prevalence of treatment-related outcomes and side effects for men diagnosed with localized prostate cancer in LMICs.

How the Research Was Conducted

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), with registration number CRD42024486632.

The review focused on men with clinically diagnosed localized prostate cancer. Localized prostate cancer was defined as non-metastatic lesions. That means tumors confined to the prostate gland, with or without spread just outside the prostate, and without involvement of regional lymph nodes or distant metastasis.

Studies from LMICs were categorized using World Bank Group income levels:

• Low-income countries: gross national income (GNI) per capita of $1,135 or less
• Lower-middle-income countries: GNI between $1,136 and $4,465
• Upper-middle-income countries: GNI between $4,466 and $13,845

All definitive treatments for localized prostate cancer were considered. However, publications not written in English were excluded.

The researchers searched the Cochrane Library, Embase, and Medline for eligible articles. These electronic databases were chosen because they are continuously updated with new publications. The researchers also hand-searched the reference lists of included studies and other systematic reviews to find additional relevant articles.

An initial search strategy was developed in Cochrane Library and then adapted for Medline and Embase. The search used terms associated with these phrases: "prostate neoplasm," "prostate cancer treatment," and "low- and middle-income countries." The Boolean operators "AND" and "OR" were used to combine search terms. These terms were combined in free text searches, titles, abstracts, and medical subject headings. Two reviews were used to create the search terms. The searches were done on 2 February 2024 and rerun on 24 February 2024.

All citation hits from the electronic database searches were exported to EndNote Version 20 for management. After removing duplicates, titles and abstracts were screened for relevant articles using the study's eligibility criteria. Two independent reviewers screened the results and reconciled them to obtain the full-text articles. Articles that did not meet the inclusion criteria were excluded with justification. Any differences between the two review authors were settled by discussion. When a consensus was not reached, two additional reviewers were consulted.

A data extraction form was created in Excel. The form captured study characteristics: author, publication year, setting, study objective, study design, sample size, age group, treatment type, assessment tool, follow-up, risk groups, staging, and Gleason score. The form also captured survival, mortality, metastasis, and biochemical failure. The form captured acute and late genitourinary and gastrointestinal toxicities. For each study, data were extracted by two reviewers. Accuracy and consensus were checked by a third reviewer.

Two review authors assessed the quality of the included studies. Disagreements were resolved through discussion. The Critical Appraisal Skills Programme and the Joanna Briggs Institute-specific study design checklist were used to appraise the included studies. Quality assessment scores equal to or below 60% were considered low quality, and scores above 60% were considered high quality. All included studies had high quality, with scores greater than 74%.

Meta-analysis was performed using a random effects model at 95% confidence intervals (95%-CIs). Effect sizes were generated from the pooled prevalence of the individual studies. Standard errors were estimated based on a formula where P is the sample proportion and n represents the sample size.

Study heterogeneity (how much the studies differed from each other) was assessed using the I² index. The categories were:

• No heterogeneity: 0%
• Low heterogeneity: 25% to 50%
• Moderate heterogeneity: 51% to 75%
• High heterogeneity: greater than 75%

Heterogeneity was considered significant at a probability value of 0.05. Forest plots and tables were generated to visualize the results. The meta-analysis was performed in Review Manager (RevMan) version 5.4.1.

What Studies Were Included

Searches from electronic databases yielded 1,882 references. After eliminating 403 duplicates, 1,479 references remained for title and abstract screening. Guided by the eligibility criteria, 1,378 articles were excluded. Eight articles could not be retrieved. Therefore, 93 full-text articles were assessed. Twenty-one articles were eligible, and 3 additional papers were found by hand search. In total, 24 records reporting on outcomes and side effects after treatment of men with localized prostate cancer were included in this review.

The study designs of the included studies were:

• 2 clinical trials
• 20 cohort studies (15 retrospective and 5 prospective)
• 1 cross-sectional study
• 1 case series

The cumulative sample size of the included studies was 2,820 patients. This total included 1,862 patients treated with radiation therapy, 948 patients treated with radical prostatectomy, and 10 patients treated with cryotherapy.

The radiation treatments used across the studies were:

• 3D-CRT: 9 studies
• Intensity modulated radiation therapy (IMRT): 2 studies
• Stereotactic body radiation therapy (SBRT): 2 studies
• 2-dimensional radiation therapy (2D-RT): 2 studies
• High dose-rate (HDR) brachytherapy: 3 studies
• Low dose-rate (LDR) brachytherapy: 2 studies

For surgery, robotic-assisted radical prostatectomy (RARP) was used in 2 studies, and retropubic radical prostatectomy (RRP) was used in 5 studies. Three studies combined EBRT with brachytherapy.

All studies provided hormonal treatment to between 5% and 97% of their included participants, except 5 studies that did not report on hormonal therapy.

The included studies were conducted across 11 LMICs:

• Brazil: 7 studies
• India: 4 studies
• Ghana: 3 studies
• Pakistan: 2 studies
• Serbia: 2 studies
• Iran: 1 study
• Malaysia: 1 study
• Peru: 1 study
• Puerto Rico: 1 study
• Russia: 1 study
• Indonesia: 1 study

Follow-Up Time and How Side Effects Were Measured

The average follow-up time across the studies was less than 5 years. However, 2 studies followed patients for 10 years or more. Two other studies followed patients for just 12 and 15 months.

Acute toxicity was measured within 90 days from the start of treatment, and late toxicity was measured beyond 90 days after treatment in 9 studies. In one study, acute toxicity was measured within 120 days from the start of treatment, and late toxicity was measured beyond 120 days after treatment. Another study measured acute toxicity within 180 days from the start of treatment and late toxicity beyond 180 days after treatment.

Tools Used to Measure Side Effects

Three assessment tools were used to measure side effects reported by clinicians:

• Radiation Therapy Oncology Group (RTOG) criteria: 8 studies
• Common Terminology Criteria for Adverse Events (CTCAE) / National Cancer Institute Common Toxicity Criteria (NCI CTC) version 4.0: 4 studies
• Clavien-Dindo classification: 2 studies

Five patient-reported side effect assessment tools were also used:

• International Prostate Symptom Score (IPSS): 4 studies
• International Index of Erectile Function (IIEF-15/16): 2 studies
• Expanded Prostate Cancer Index Composite (EPIC) Questionnaire: 2 studies
• European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ) C30: 1 study
• Medical Outcome Study 8-item Short-form Health Survey (SF-8): 1 study

Results After External Beam Radiation Therapy (EBRT)

After 3D-CRT, the most common clinician-reported side effects were grade 1 toxicities. Grade 1 means a mild side effect. The rates were:

• Acute skin grade 1: 46%
• Acute genitourinary (urinary) grade 1: 29%
• Acute gastrointestinal (bowel) grade 1: 24%
• Late gastrointestinal (bowel) grade 1: 18%

Serious side effects were uncommon after 3D-CRT. Acute and late genitourinary grade 3 and gastrointestinal grade 3 toxicities were below 3%. No grade 4 toxicities were reported after 3D-CRT. Grade 3 means a severe side effect, and grade 4 means a life-threatening side effect.

Acute gastrointestinal (bowel) toxicities. Four studies with 340 patients who underwent 3D-CRT provided data on acute bowel toxicity. The pooled prevalence of acute gastrointestinal grades 1 to 3 toxicities was:

• Grade 1: 24% (95% CI, 8%-41%; I² = 94%, P < .00001)
• Grade 2: 17% (95% CI, 3%-31%; I² = 95%, P < .00001)
• Grade 3: 1% (95% CI, 0%-3%; I² = 9%, P = .33)

Late gastrointestinal (bowel) toxicities. Four studies provided data on late bowel toxicity for patients who underwent 3D-CRT. The pooled prevalence of late gastrointestinal grades 1 to 3 toxicities was:

• Grade 1: 18% (95% CI, 5%-32%; I² = 95%, P < .00001)
• Grade 2: 3% (95% CI, 0%-6%; I² = 64%, P = .04)
• Grade 3: 2% (95% CI, 0%-3%; I² = 0%, P = .62)

It was not possible to perform a meta-analysis on acute and late gastrointestinal toxicities for the single studies that evaluated 2D-RT, IMRT, and SBRT.

Acute genitourinary (urinary) toxicities. Three studies with 246 patients who underwent 3D-CRT provided data on acute urinary toxicity. The pooled prevalence of acute genitourinary grades 1 to 3 toxicities was:

• Grade 1: 29% (95% CI, 12%-47%; I² = 91%, P < .00001)
• Grade 2: 16% (95% CI, 1%-31%; I² = 93%, P < .00001)
• Grade 3: 3% (95% CI, 0%-5%; I² = 41%, P = .18)

Late genitourinary (urinary) toxicities. Three studies with 246 patients who underwent 3D-CRT provided data on late urinary toxicity. The pooled prevalence of late genitourinary grades 1 to 3 toxicities was:

• Grade 1: 13% (95% CI, 1%-24%; I² = 91%, P < .00001)
• Grade 2: 2% (95% CI, 0%-3%; I² = 0%, P = .32)
• Grade 3: 2% (95% CI, 0%-4%; I² = 0%, P = 1)

It was not possible to perform a meta-analysis on acute and late genitourinary toxicity for the single studies that evaluated 2D-RT, IMRT, and SBRT.

Acute skin toxicities. Two studies with 135 patients who underwent 3D-CRT provided data on acute skin toxicity. The pooled prevalence of acute skin grades 1 to 3 toxicities was:

• Grade 1: 46% (95% CI, 7%-85%; I² = 96%, P < .00001)
• Grade 2: 14% (95% CI, 0%-30%; I² = 84%, P = .01)
• Grade 3: 1% (95% CI, 0%-3%; I² = 0%, P = .65)

It was not possible to perform a meta-analysis on the acute skin toxicity for the single studies that evaluated other radiation techniques.

Results After Brachytherapy

In the brachytherapy group, the prevalence of acute genitourinary grade 1 toxicity was 19%. Brachytherapy places radioactive material directly inside or next to the prostate. This treatment was used alone or in combination with EBRT in the included studies.

Three studies combined EBRT with brachytherapy. The combined approach was associated with a 5-year overall survival rate of 96%, which was higher than the 87% seen after 3D-CRT alone.

Results After Radical Prostatectomy

Perioperative rectal injury (rectal injury occurring during or around the time of surgery) was the least prevalent side effect after retropubic radical prostatectomy, at 2%. Radical prostatectomy is surgical removal of the prostate gland.

The 4-year biochemical failure rate after radical prostatectomy was 22%. Biochemical failure means a rise in PSA that suggests the cancer may be returning.

Survival and Cancer Control Outcomes

The study reported several key cancer control outcomes:

• After 3D-CRT, the 5-year overall survival rate was 87%.
• For the combined brachytherapy and EBRT group, the 5-year overall survival rate increased to 96%.
• The prevalence of 5-year biochemical failure following EBRT was 18%.
• The prevalence of 5-year biochemical failure following brachytherapy was 30%.
• The 4-year biochemical failure after radical prostatectomy was 22%.
• The 3-year biochemical failure after combined EBRT with brachytherapy was 2%.

These numbers show that most men with localized prostate cancer in LMICs had good cancer control after treatment. The combined brachytherapy and EBRT approach was associated with the highest 5-year overall survival rate.

What These Findings Mean for Patients

This systematic review and meta-analysis indicates that in LMICs, EBRT, brachytherapy, and radical prostatectomy, used alone or in combination, have excellent potential for localized prostate cancer control. The treatments were associated with low rates of side effects and good cancer outcomes.

For patients, these findings are encouraging. Most side effects after 3D-CRT were mild (grade 1). Serious side effects (grade 3) were uncommon, affecting fewer than 3 in 100 patients for urinary and bowel problems. No life-threatening (grade 4) side effects were reported after 3D-CRT.

The results of this review can help policymakers, patients, and clinicians make informed decisions to strengthen prostate cancer care in LMICs. Men diagnosed with localized prostate cancer in these regions can discuss these treatment options with their doctors, knowing that the expected side effects are generally manageable.

Limitations of the Study

The study had several limitations. The average follow-up time across most studies was less than 5 years, which limits what can be said about long-term outcomes. Two studies followed patients for 10 years or more, but two other studies followed patients for only 12 and 15 months.

There was high heterogeneity (variation) between studies for many of the pooled results. For example, the I² values for acute gastrointestinal grade 1 toxicity (94%), acute genitourinary grade 1 toxicity (91%), and acute skin grade 1 toxicity (96%) were all high. This means the studies differed substantially from each other in their results.

It was not possible to perform meta-analyses for several treatment types because only single studies evaluated them. These included 2D-RT, IMRT, and SBRT for gastrointestinal and genitourinary toxicities, and other radiation techniques for skin toxicity.

The review excluded non-English publications, which may have left out relevant studies. The included studies also varied in how they measured and reported side effects, using different assessment tools and different time periods for defining acute versus late toxicity.

Recommendations for Patients and Health Systems

The authors concluded that efforts are required to improve several aspects of prostate cancer care in LMICs. These efforts aim to minimize treatment side effects and improve outcomes for localized prostate cancer.

The authors recommended the following actions:

1. Improve early detection of prostate cancer through awareness campaigns and targeted screening programs.
2. Improve treatment accessibility so that men in LMICs can receive timely and appropriate care.
3. Provide regular post-treatment follow-up care to monitor for side effects and cancer recurrence.
4. Maintain consistent quality assurance practices in radiation therapy and surgery.
5. Support continued staff development and training to help minimize treatment side effects.

For patients, the key message is that treatment for localized prostate cancer in LMICs is generally effective and well tolerated. Men should discuss all treatment options with their healthcare team. They should also attend regular follow-up appointments after treatment. These appointments help doctors detect any returning cancer early and manage any side effects.

Patients who experience side effects during or after treatment should tell their healthcare team. Most side effects are mild and can be managed with supportive care. Serious side effects are uncommon, but patients should still report any concerning symptoms promptly.

Frequently Asked Questions

What treatments were studied for localized prostate cancer in low- and middle-income countries?

A review of 24 studies covering 2,820 men in 11 low- and middle-income countries looked at external beam radiation therapy, brachytherapy (radioactive seeds placed inside the prostate), radical prostatectomy (surgical removal of the prostate), and cryotherapy. Radiation techniques included 3D-CRT, IMRT, SBRT, and 2D-RT. Some men also received hormone therapy alongside these treatments.

What side effects are common after 3D-CRT for localized prostate cancer?

After 3-dimensional conformal radiation therapy, the most common side effects were mild (grade 1). These included acute skin reactions in 46% of men, acute urinary problems in 29%, acute bowel problems in 24%, and late bowel problems in 18%. Serious grade 3 urinary and bowel side effects occurred in fewer than 3% of men, and no life-threatening grade 4 side effects were reported.

What were the survival rates after radiation treatments?

Five-year overall survival was 87% after 3D-CRT alone and 96% after combined brachytherapy plus external beam radiation therapy. The review included 2,820 men with localized prostate cancer in low- and middle-income countries. These numbers reflect the pooled results from the included studies, not a guarantee for any individual patient.

What side effects occurred after radical prostatectomy?

After retropubic radical prostatectomy, perioperative rectal injury (rectal injury during or around the time of surgery) was the least prevalent side effect, occurring in 2% of men. The four-year biochemical failure rate after radical prostatectomy was 22%. The review included 948 patients treated with radical prostatectomy across the included studies.

What should patients do after treatment for localized prostate cancer?

Patients should discuss all treatment options with their healthcare team and attend regular follow-up appointments after treatment. These visits help doctors detect any returning cancer early and manage side effects. Patients who experience side effects during or after treatment should tell their healthcare team, because most side effects are mild and can be managed with supportive care.

I have localized prostate cancer and my doctor recommends radiation — when should I get a second opinion on the treatment plan?

A second opinion is reasonable when the recommended treatment is 3D-CRT, brachytherapy, radical prostatectomy, or a combination, because these options differ in outcomes. Five-year overall survival is 87% after 3D-CRT alone and 96% after combined brachytherapy plus EBRT, while 5-year biochemical failure is 18% after EBRT and 30% after brachytherapy. Most side effects after 3D-CRT are mild grade 1, and serious grade 3 urinary and bowel effects stay below 3%. Reviewing these trade-offs with another expert can clarify which approach fits your situation. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Outcomes and Toxicities After Treatment for Men Diagnosed With Localized Prostate Cancer in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.

Authors: Kitson-Mills D, Donkor A, Amoako YA, Kyei KA, Bonsu EBO, Vanderpuye V, Wiafe YA.

Author affiliations: Department of Medical Imaging, Faculty of Allied Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana; Improving Palliative, Aged and Chronic Care through Clinical Research and Translation (IMPACCT), Faculty of Health, University of Technology Sydney, Sydney, New South Wales, Australia; Department of Medicine, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana; Department of Radiography, School of Biomedical and Allied Health Sciences, University of Ghana, Accra, Ghana; National Radiotherapy and Nuclear Medicine Centre, Komfo Anokye Teaching Hospital, Kumasi, Ghana; and National Centre for Radiotherapy Oncology Nuclear Medicine, Korle-Bu Teaching Hospital, Accra, Ghana

Journal: Advances in Radiation Oncology (2025) 10, 101670

Article type: Critical Review

Publication history: Received 22 May 2024; accepted 21 October 2024

Funding: This work had no specific funding.

Data sharing: The data is shared along with the study.

Corresponding author: Doris Kitson-Mills, MPH, MPhil; Email: d.kitsonmills@knust.edu.gh

DOI: https://doi.org/10.1016/j.adro.2024.101670

Copyright: © 2024 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This patient-friendly article is based on peer-reviewed research.