External Beam Radiotherapy for Prostate Cancer Patients on Anticoagulation Therapy: How Significant is the Bleeding Toxicity?

doi:10.1016/j.ijrobp.2009.02.026

International Journal of Radiation OncologyBiologyPhysics

Volume 76, Issue 3, 1 March 2010, Pages 755-760

Presented at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Los Angeles, CA, October 28 to November 1, 2007.

https://doi.org/10.1016/j.ijrobp.2009.02.026 Get rights and content

Purpose

To characterize the bleeding toxicity associated with external beam radiotherapy for prostate cancer patients receiving anticoagulation (AC) therapy.

Methods and Materials

The study cohort consisted of 568 patients with adenocarcinoma of the prostate who were treated with definitive external beam radiotherapy. Of these men, 79 were receiving AC therapy with either warfarin or clopidogrel. All patients were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Bleeding complications were recorded during treatment and subsequent follow-up visits.

Results

With a median follow-up of 48 months, the 4-year actuarial risk of Grade 3 or worse bleeding toxicity was 15.5% for those receiving AC therapy compared with 3.6% among those not receiving AC (p < .0001). On multivariate analysis, AC therapy was the only significant factor associated with Grade 3 or worse bleeding (p < .0001). For patients taking AC therapy, the crude rate of bleeding was 39.2%. Multivariate analysis within the AC group demonstrated that a higher radiotherapy dose (p = .0408), intensity-modulated radiotherapy (p = 0.0136), and previous transurethral resection of the prostate (p = .0001) were associated with Grade 2 or worse bleeding toxicity. Androgen deprivation therapy was protective against bleeding, with borderline significance (p = 0.0599). Dose–volume histogram analysis revealed that Grade 3 or worse bleeding was minimized if the percentage of the rectum receiving ≥70 Gy was <10% or the rectum receiving ≥50 Gy was <50%.

Conclusion

Patients taking AC therapy have a substantial risk of bleeding toxicity from external beam radiotherapy. In this setting, dose escalation or intensity-modulated radiotherapy should be used judiciously. With adherence to strict dose–volume histogram criteria and minimizing hotspots, the risk of severe bleeding might be reduced.

Introduction

Prostate cancer is the most common non–skin malignancy in men, and it is estimated that more than 180,000 new cases will have been diagnosed in 2008 (1). The incidence of prostate cancer increases as men age, to as much as 1 in 7 among those older than 70 years (1). External beam radiotherapy (EBRT) is one of the standard treatment options for localized prostate cancer, and it might be the preferred treatment option when treating men with significant comorbidities. Although EBRT is usually well tolerated, bleeding from radiation proctitis or cystitis is a common and potentially serious complication of EBRT.

In recent years, several studies have shown better biochemical outcomes after dose-escalated EBRT 2, 3, 4. The use of three-dimensional conformal RT and more recently, intensity-modulated RT (IMRT) has allowed the delivery of escalated radiation doses with more normal tissue sparing; however, rectal- and bladder-related toxicities remain a challenge 5, 6, 7. Several clinical and treatment factors have been associated with rectal and bladder bleeding, including a high radiation dose, mean rectal dose, whole pelvic RT (WPRT), previous transurethral resection of the prostate (TURP), and androgen deprivation therapy (ADT) 7, 8, 9, 10, 11, 12. Although data are limited, it is logical to assume that anticoagulation (AC) therapy can also significantly influence the risk of bleeding. In one prospective study of 57 men undergoing EBRT for prostate cancer, 4 developed Grade 3 rectal bleeding toxicity, and all had been taking AC agents with either warfarin or high-dose aspirin (13).

Anticoagulation therapy is required for many patients with cardiovascular disorders, such as ischemic heart disease, atrial fibrillation, valvular disease, and venous thromboembolism. These disorders are much more prevalent in the elderly population, similar to prostate cancer. Bleeding is a common complication of AC therapy, and for men undergoing EBRT for prostate cancer, the bleeding toxicity is expected to be greater. To investigate the risk of bleeding toxicity and to identify the potentially modifiable factors, we reviewed our experience of treating prostate cancer patients who were receiving AC therapy.

Section snippets

Methods and Materials

The present study included patients with adenocarcinoma of the prostate, who had been treated with definitive EBRT at the University of Chicago Pritzker School of Medicine between 1988 and 2005. The other inclusion criteria were no evidence of metastatic disease, ≥2 years of potential follow-up, and no prostatectomy or brachytherapy as a component of treatment. Patients were excluded if they had no documented list of medications (n = 54). Patients were assigned to the AC group if they had

Patient characteristics

The patient characteristics and treatment details are summarized in Table 1. The two groups had similar patient, disease, and treatment characteristics. Specifically, no differences were found in median age, median follow-up time, or the disease risk categories. The use of IMRT was more common in the AC group, and the median radiation dose in the AC group was slightly greater. However, the mean and maximal rectal doses did not differ significantly among those for whom data were available.

Of the

Discussion

With recent advances in RT techniques, such as IMRT and image-guided RT, greater doses of EBRT can be delivered more safely in treating prostate cancer. However, bleeding from radiation-induced injury is still a possible complication, limiting further escalation of the radiation dose. Because prostate cancer is typically a disease affecting the elderly, these patients might also have cardiovascular conditions that require lifelong AC therapy. In the setting of AC therapy, the bleeding toxicity

Conclusion

The results of our study have revealed that patients taking warfarin or clopidogrel are at a substantial risk of acute and late bleeding toxicity when treated with EBRT for prostate cancer. Given this risk, special care is warranted when considering the most appropriate radiation dose, target volume, and DVH criteria for men receiving AC therapy. Additionally, any future analyses relating DVH criteria with late bleeding toxicity should be mindful to exclude or make special consideration for

References (26)

A. Pollack et al.
Prostate cancer radiation dose response: Results of the M.D. Anderson phase III randomized trial
Int J Radiat Oncol Biol Phys
(2002)
M.J. Zelefsky et al.
Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer
Int J Radiat Oncol Biol Phys
(2008)
S.T. Peeters et al.
Acute and late complications after radiotherapy for prostate cancer: Results of a multicenter randomized trial comparing 68 Gy to 78 Gy
Int J Radiat Oncol Biol Phys
(2005)
T. Teshima et al.
Rectal bleeding after conformal 3D treatment of prostate cancer: Time to occurrence, response to treatment and duration of morbidity
Int J Radiat Oncol Biol Phys
(1997)
V. Vavassori et al.
Predictors for rectal and intestinal acute toxicities during prostate cancer high-dose 3D-CRT: Results of a prospective multicenter study
Int J Radiat Oncol Biol Phys
(2007)
A. Zapatero et al.
Impact of mean rectal dose on late rectal bleeding after conformal radiotherapy for prostate cancer: Dose–volume effect
Int J Radiat Oncol Biol Phys
(2004)
A. Zapatero et al.
Is hormone therapy a protective factor for late hematuria after high-dose radiotherapy in prostate cancer?
Urology
(2008)
A.V. D∼Amico et al.
A prospective evaluation of rectal bleeding after dose-escalated three-dimensional conformal radiation therapy using an intrarectal balloon for prostate gland localization and immobilization
Urology
(2006)
J.D. Cox et al.
Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC)
Int J Radiat Oncol Biol Phys
(1995)
C.A. Lawton et al.
Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706
Int J Radiat Oncol Biol Phys
(1991)

H.M. Sandler et al.

Three dimensional conformal radiotherapy for the treatment of prostate cancer: Low risk of chronic rectal morbidity observed in a large series of patients

Int J Radiat Oncol Biol Phys

(1995)

S.T. Peeters et al.

Volume and hormonal effects for acute side effects of rectum and bladder during conformal radiotherapy for prostate cancer

Int J Radiat Oncol Biol Phys

(2005)

R. Valdagni et al.

Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3D-CRT

Int J Radiat Oncol Biol Phys

(2008)

Cited by (67)

Mechanisms, mitigation, and management of urinary toxicity from prostate radiotherapy
2022, The Lancet Oncology
Urinary toxicity is common following pelvic radiotherapy and can have a substantial negative effect on survivorship. Due to its prevalence and the increasing number of related clinical trials, localised prostate cancer radiotherapy is a useful illustrative tool to explore urinary toxicity. A good understanding of the interplay between anatomy, radiation-sensitive cell populations, and treatment sequencing is necessary for optimal outcomes. Emerging evidence suggests that the prostatic urethra is a radiation-sensitive structure, not only for stricture development, but also chronic irritative symptoms. Tools now exist not only to identify the urethra, but also to direct radiation dose away from the urethra, with early data suggesting that this reduces moderate-to-severe late urinary toxicity. Coupled with new evidence supporting dominant nodule microboosting and ultrahypofractionation as emerging standards of care, urethral sparing radiotherapy is a powerful tool against radiation induced urinary toxicity while also maximising disease control.
Late genitourinary and gastrointestinal toxicity and radiation-induced second primary cancers in patients treated with low-dose-rate brachytherapy
2022, Brachytherapy
Citation Excerpt :
The association between age and GI toxicity may be explained by other factors not included in the present study, such as hemorrhoids and anticoagulation therapy. Importantly, hemorrhoids (26) and anticoagulation therapy (31) have been reported as significant factors related to GI toxicity, and the incidence of hemorrhoids (32) and anticoagulation therapy (33) is higher in older patients than in younger patients. However, we did not include these 2 variables in the analyses, which is a limitation of the present study.
To evaluate late genitourinary (GU) and gastrointestinal (GI) toxicities and radiation-induced second primary cancers (RISPCs) in patients who received low-dose-rate brachytherapy (LDR-BT) with or without external beam radiotherapy for prostate cancer.
This retrospective study included 897 consecutive patients who received LDR-BT between July 2004 and July 2015 in our institution. Adverse events and the incidence of second primary cancers were evaluated at 1, 3, 6, 12, 18, 24, 30, 36, 48, 54, and 60 mo after LDR-BT and then once a year. Related factors to ≥grade 2 (G2) toxicity were evaluated using the Cox proportional-hazards model.
The median follow-up time was 85.2 (interquartile range: 66.8–111.3) mo. The cumulative incidence rates of ≥G2 GU toxicity at 5 and 10 yrs after LDR-BT were 11.2% and 14.7%, respectively. The International Prostate Symptom Score before LDR-BT (continuous) (hazard ratio [HR]: 1.03), no neoadjuvant androgen deprivation therapy (HR: 1.69), and combination external beam radiotherapy (HR: 3.30) were risk factors related to the incidence of ≥G2 GU toxicity. The cumulative incidence rates of ≥G2 GI toxicity at 5 and 10 yrs after LDR-BT were 3.3% and 3.3%, respectively. Age (continuous) (HR: 1.09), body mass index (continuous) (HR: 0.87), and rectum V100 (continuous) (HR: 1.64) were risk factors related to ≥G2 GI toxicity. A total of 12 (1.3%) patients developed metachronous RISPCs (bladder cancer: 9; rectal cancer: 3).
The incidence rates of late GU and GI toxicities and RISPCs after LDR-BT were low.
Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer
2022, Radiotherapy and Oncology
Genome-wide association studies (GWAS) of late hematuria following prostate cancer radiotherapy identified single nucleotide polymorphisms (SNPs) near AGT, encoding angiotensinogen. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEi) have a reduced risk of late hematuria. We additionally tested genetically-defined hypertension.
Prostate cancer patients undergoing potentially-curative radiotherapy were enrolled onto two multi-center observational studies, URWCI (N = 256) and REQUITE (N = 1,437). Patients were assessed pre-radiotherapy and followed prospectively for development of toxicity for up to four years. The cumulative probability of hematuria was estimated by the Kaplan-Meier method. Multivariable grouped relative risk models assessed the effect of ACEi on time to hematuria adjusting for clinical factors and stratified by enrollment site. A polygenic risk score (PRS) for blood pressure was tested for association with hematuria in REQUITE and our Radiogenomics Consortium GWAS.
Patients taking ACEi during radiotherapy had a reduced risk of hematuria (HR 0.51, 95%CI 0.28 to 0.94, p = 0.030) after adjusting for prior transurethral prostate and/or bladder resection, heart disease, pelvic node radiotherapy, and bladder volume receiving 70 Gy, which are associated with hematuria. A blood pressure PRS was associated with hypertension (odds ratio per standard deviation 1.38, 95%CI 1.31 to 1.46, n = 5,288, p < 0.001) but not hematuria (HR per standard deviation 0.96, 95%CI 0.87 to 1.06, n = 5,126, p = 0.41).
Our study is the first to show a radioprotective effect of ACEi on bladder in an international, multi-site study of patients receiving pelvic radiotherapy. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects the bladder.
Dose-Based Radiomic Analysis (Dosiomics) for Intensity Modulated Radiation Therapy in Patients With Prostate Cancer: Correlation Between Planned Dose Distribution and Biochemical Failure
2022, International Journal of Radiation Oncology Biology Physics
Although radiation therapy is one of the most significant treatment modalities for localized prostate cancer, the prognostic factors for biochemical recurrence (BCR) regarding the treatment plan are unclear. We aimed to develop a novel dosiomics-based prediction model for BCR in patients with prostate cancer and clarify the correlations between the dosimetric factors and BCR.
This study included 489 patients with localized prostate cancer (BCR: 96; no-BCR: 393) who received intensity modulated radiation therapy. A total of 2475 dosiomic features were extracted from the dose distributions on the prostate, clinical target volume (CTV), and planning target volume. A prediction model for BCR was trained on a training cohort of 342 patients. The performance of this model was validated using the concordance index (C-index) in a validation cohort of 147 patients. Another model was constructed using clinical variables, dosimetric parameters, and radiomic features for comparisons. Kaplan-Meier curves with log-rank analysis were used to assess the univariate discrimination based on the predictive dosiomic features.
The dosiomic feature derived from the CTV was significantly associated with BCR (hazard ratio, 0.73; 95% CI, 0.57-0.93; P = .01). Although the dosiomics model outperformed the dosimetric and radiomics models, it did not outperform the clinical model. The performance significantly improved by combining the clinical variables and dosiomic features (C-index: 0.67; 95% CI, 0.65-0.68; P < .0001). The predictive dosiomic features were used to distinguish high-risk and low-risk patients (P < .05).
The dosiomic feature extracted from the CTV was significantly correlated with BCR in patients with prostate cancer, and the dosiomics model outperformed the model with conventional dose indices. Hence, new metrics for evaluating the quality of a treatment plan are warranted. Moreover, further research should be conducted to determine whether dosiomics can be incorporated in a clinical workflow or clinical trial.
Advances in radiotherapy in bone metastases in the context of new target therapies and ablative alternatives: A critical review
2021, Radiotherapy and Oncology
In patients with bone metastases (BM), radiotherapy (RT) is used to alleviate symptoms, reduce the risk of fracture, and improve quality of life (QoL). However, with the emergence of concepts like oligometastases, minimal invasive surgery, ablative therapies such as stereotactic ablative RT (SABR), radiosurgery (SRS), thermal ablation, and new systemic anticancer therapies, there have been a paradigm shift in the multidisciplinary approach to BM with the aim of preserving mobility and function survival.
Despite guidelines on using single-dose RT in uncomplicated BM, its use remains relatively low. In uncomplicated BM, single-fraction RT produces similar overall and complete response rates to RT with multiple fractions, although it is associated with a higher retreatment rate of 20% versus 8%.
Complicated BM can be characterised as the presence of impending or existing pathologic fracture, a major soft tissue component, existing spinal cord or cauda equina compression and neuropathic pain. The rate of complicated BM is around 35%. Unfortunately, there is a lack of prospective trials on RT in complicated BM and the best dose/fractionation regimen is not yet established.
There are contradictory outcomes in studies reporting BM pain control rates and time to pain reduction when comparing SABR with Conventional RT. While some studies showed that SABR produces a faster reduction in pain and higher pain control rates than conventional RT, other studies did not show differences. Moreover, the local control rate for BM treated with SABR is higher than 80% in most studies, and the rate of grade 3 or 4 toxicity is very low. The use of SABR may be preferred in three circumstances: reirradiation, oligometastatic disease, and radioresistant tumours. Local ablative therapies like SABR can delay change or use of systemic therapy, preserve patients' Qol, and improve disease-free survival, progression-free survival and overall survival. Moreover, despite the potential benefit of SABR in oligometastatic disease, there is a need to establish the optial indication, RT dose fractionation, prognostic factors and optimal timing in combination with systemic therapies for SABR.
This review evaluates the role of RT in BM considering these recent treatment advances. We consider the definition of complicated BM, use of single and multiple fractions RT for both complicated and uncomplicated BM, reirradiation, new treatment paradigms including local ablative treatments, oligometastatic disease, systemic therapy, physical activity and rehabilitation.
Pelvic Complications After Prostate Cancer Radiation Therapy and Their Management: An International Collaborative Narrative Review(Figure presented.)
2019, European Urology
Radiotherapy used for treating localized prostate cancer is effective at prolonging cancer-specific and overall survival. Still, acute and late pelvic toxicities are a concern, with gastrointestinal (GI) and genitourinary (GU) sequelae being most common as well as other pelvic complications.
To present a critical review of the literature regarding the incidence and risk factors of pelvic toxicity following primary radiotherapy for prostate cancer and to provide a narrative review regarding its management.
A collaborative narrative review of the literature from 2010 to present was conducted.
Regardless of the modality used, the incidence of acute high-grade pelvic toxicity is low following conventionally fractionated external beam radiotherapy (EBRT). After moderate hypofractionation, the crude cumulative incidences for late grade 3 or higher (G3+) GI and GU complications are as high as 6% and 7%, respectively. After extreme hypofractionation, the 5-yr incidences of G2+ GU and GI toxicities are 3–9% and 0–4%, respectively. Following brachytherapy monotherapy, crude rates of late G3+ GU toxicity range from 6% to 8%, while late GI toxicity is rare. With combination therapy (EBRT and brachytherapy), the cumulative incidence of late GU toxicity is high, between 18% and 31%; however, the prevalence is lower at 4–14%. Whole pelvic radiotherapy remains a controversial treatment option as there is increased G3+ GI toxicity compared with prostate-only treatment, with no overall survival benefit. Proton beam therapy appears to have similar toxicity to photon therapies currently in use. With respect to specific complications, urinary obstruction and urethral stricture are the most common severe urinary toxicities. Rectal and urinary bleeding can be recurrent long-term toxicities. The risk of hip fracture is also increased following prostate radiotherapy. The literature is mixed on the risk of in-field secondary pelvic malignancies following prostate radiotherapy. Urinary and GI fistulas are rare complications. Management of these toxicities may require invasive treatment and reconstructive surgery for refractory and severe symptoms.
There has been progress in the delivery of radiotherapy, enabling the administration of higher doses with minimal tradeoff in terms of slightly increased or equal toxicity. There is a need to focus future improvements in radiotherapy on sparing critical structures to reduce GU and GI morbidities. While complications such as fistulae, bone toxicity, and secondary malignancy are rare, there is a need for higher-quality studies assessing these outcomes and their management.
In this report, we review the literature regarding pelvic complications following modern primary prostate cancer radiotherapy and their management. Modern radiotherapy technologies have enabled the administration of higher doses with minimal increases in toxicity. Overall, high-grade long-term toxicity following prostate radiotherapy is uncommon. Management of late high-grade pelvic toxicities can be challenging, with patients often requiring invasive therapies for refractory cases.

View all citing articles on Scopus

: Conflict of interest: none.

View full text

Clinical InvestigationExternal Beam Radiotherapy for Prostate Cancer Patients on Anticoagulation Therapy: How Significant is the Bleeding Toxicity?

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Methods and Materials

Patient characteristics

Discussion

Conclusion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Urology

Urology

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical Investigation
External Beam Radiotherapy for Prostate Cancer Patients on Anticoagulation Therapy: How Significant is the Bleeding Toxicity?