Current trends in prostate cancer: The role of brachytherapy

Prostate cancer is the most prevalent cancer in men who are nonsmokers, with an incidence of about 165,000 cases reported annually. Although most of these patients will die from other causes, given the sheer volume, the disease ranks second in cancer deaths among men—approximately 30,000 annually, which represents a steady decline from its peak in 1993. For all stages combined, the five-year survival rate is the highest of all cancers that affect men. Yet by age 80, it is the leading cause of cancer death in men.1

The etiology of most prostate cancer is unknown. Diets high in fat, calcium, and dairy may be risk factors. Increasing age is a risk factor, with the disease more common in men older than age 50. Autopsy series have found prostate cancer cells in 39 percent of men ages 70–79.2 Family history is relevant not just as a risk factor, but because of a correlation with aggressiveness. Men with two immediate family members with the disease have an increased likelihood of developing higher-risk cancer.3

Prostate cancer can present with symptoms or with an abnormal digital rectal examination, but it is most commonly detected by an abnormal elevation of the prostate-specific antigen (PSA) level. This ability to identify the cancer when asymptomatic offers both opportunities as well as challenges. As with most cancers, early detection can translate into improved survival rates. Nonetheless, many men are destined to die with, but not from, this cancer. It is therefore incumbent upon clinicians to address quality of life (QOL) considerations as well as survival.

Staging and options for management

The American Joint Committee on Cancer Eighth Edition Cancer Staging Manual classifies the disease into one of four stage groups, with subdivisions based on three criteria: anatomic extent (tumor-node-metastasis categories), PSA level, and grade.4 These factors, along with life expectancy, form the basis for deciding how to best approach a patient’s prostate cancer.

Options for management of nonmetastatic disease include active surveillance (AS), surgery, and radiotherapy with or without androgen deprivation therapy (ADT). Treatment decisions must account for logistics, convenience, cost, QOL, and personal preferences in light of the equivalence in survival with radiotherapy and surgery.5

Great progress has been made in all areas of management. AS has found increasing support for patients with very low, low, and favorable intermediate-risk disease and is now the preferred approach for very low-risk patients with a life expectancy of 10 to 20 years.6 With advanced robotic techniques, the radical prostatectomy (RP) has largely shifted from an open to a minimally invasive procedure. And with radiation therapy, the conventional means of delivering external beam radiation therapy (EBRT) have been replaced first with three-dimensional conformal radiation therapy or even more sophisticated technologies that use image guidance and intensity modulation. Whether given with standard doses, moderately, or extremely hypo-fractionated schedules, higher biologically effective doses are now given with less toxicity.

BT

The radiotherapeutic approach that perhaps offers the ability to be given in the highest doses in the most conformal fashion is interstitial brachytherapy (BT). Prostate BT is a procedure in which radiation is delivered directly into the gland. In the U.S., this procedure is most commonly done with a low dose rate (LDR) approach using iodine-125, along with other sources, such as palladium-103 and cesium-137, offering alternatives with increasingly shorter half-lives. Alternatively, temporary high-dose rate implants can be accomplished with iridium-192.

The advantage of LDR BT is the ability to deliver an entire course of therapy in a single 60- to 90-minute procedure with minimally invasive techniques. Little time is lost from work and other routine activities. BT can be offered to patients if the gland does not exceed 60 ccs to minimize the risk of the pubic arch interfering with optimal placement of the interstitial needles, and should be avoided in patients with significantly lower urinary tract symptoms (for example, an International Prostate Symptom Score greater than 15).

The use of BT as monotherapy is supported by the National Comprehensive Cancer Network guidelines for patients with very low, low, and favorable intermediate-risk disease. In higher risk cases, it is most often given as a boost to EBRT. Nonetheless, some data support its use as monotherapy. Jackson and colleagues studied 4,496 men with a favorable subset of high-risk disease; that is, men with a Gleason score of 8, T1c or T2a, and a PSA <10 ng/mL. Compared with EBRT, patients receiving BT, with or without EBRT, had longer overall survival rates.7

With the publication of the Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) trial,8 a brachytherapy boost (BB) following EBRT now has been supported in a randomized prospective trial for patients with intermediate- and high-risk cancer. This study found that the nine-year disease-free survival rate increased from 62 percent for patients not receiving a BB to 83 percent for patients receiving a BB. Although short-term side effects increased in the BB group, by six years the health-related QOL was similar, favoring the LDR BB group.9 Another advantage of a BB is that it allows for the total duration of ADT to be reduced from two to three years, as indicated for patients treated with EBRT alone, to as little as one year.10

Comparing the data

Both retrospective and prospective data are available to assess QOL outcomes using BT. In a wide sweep of the available published literature on comparative studies for QOL, Lardas and colleagues found no significant urinary toxicity at five years for patients receiving BT.11 Data in the North Carolina Central Cancer Registry showed that when 1,141 men in a prospective cohort were compared on the basis of QOL after RP, EBRT, and BT, each treatment had distinctive patterns of adverse effects, but by two years, the mean scores were similar in most domains.12

With excellent survival and QOL outcomes, cost considerations are relevant. To compare direct costs of prostate treatment in newly diagnosed patients, Wilson and colleagues used the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) registry and performed a longitudinal analysis of 4,553 men treated for prostate cancer. The study was for 1995–2004 and revealed that the least costly treatment was BT, intermediate was RP, and most costly was EBRT.13

In a resource-limited environment, has a shift to this less costly treatment occurred given the impressive survival and QOL outcomes? More than 1.5 million patients were analyzed in a National Cancer Database (NCDB) query for prostate cancer patients treated from 1998 to 2010. BT usage peaked in 2002 at 16.7 percent, then steadily declined to a low of 8 percent in 2010. Patients with intermediate- or high-risk cancer, increased comorbidity, and increased year of diagnosis were less likely to receive BT.14

Glaser and colleagues reported on 113,719 cases in the NCDB treated from 2004 to 2013 with intermediate- or high-risk cancer. Use of BB decreased from 33.1 percent in 2004 to 12.5 percent in 2013 for intermediate-risk patients and from 27.6 percent to 10.8 percent for high-risk patients. However, patients getting a BB had higher survival rates.15

Safdieh and colleagues identified 89,413 low-risk patients treated from 2004 to 2012 abstracted from the NCDB. A decline was noted in both academic and nonacademic facilities, with the use of BT decreasing from 62.9 percent in 2004 to 51.3 percent in 2012.16

Our analysis

Because of this discrepancy, and to carry the analysis closer to the present, the NCDB data from 2004 to 2016 were analyzed. The authors identified 1,028,470 patients with stage I and II prostate cancer. The data were aggregated into two groups. The first included stages I and IIA, men typically well-suited for BT alone. The stage IIB patients were separately reviewed given the potential benefit of using a combination of EBRT with a BB.

In the lower-risk group, slightly more patients were treated with BT rather than EBRT in 2004 (15.1 percent versus 14.2 percent). By 2016, only 5.1 percent were treated with BT, one-third the 2004 levels. Patients treated with EBRT, however, were 14.2 percent with no change during the years studied. The stage IIB patients also experienced a decline in the reliance on BT. Patients getting EBRT with a BB decreased from 6.3 percent to 3.2 percent, whereas patients treated with BT alone dropped from 5.8 percent to 2.1 percent. At the same time, use of EBRT alone increased from 17.5 percent to 19.3 percent (see Figure 1).

Figure 1. Radiation modality by stage and diagnosis year, NCDB

Conclusion

Several explanations have been offered to rationalize this decline in the use of brachytherapy, including decreasing expertise and fewer training opportunities. For example, Orio and colleagues found the percentage of academic practices performing BT decreased from 80 percent in 2004 to 65 percent in 2012, while the percentage in nonacademic practices declined from 75 percent to 55 percent in the same time frame.17 Academic and nonacademic practices performing at least 53 cases per year were few and decreased to 1.5 percent and 2.7 percent, respectively.

The economic incentives also favor EBRT over BT. Dutta and colleagues performed what they described as a time-driven and activity-based cost comparison between BT and EBRT using intensity-modulated radiation therapy. The cost of BT using LDR was $2,719 per patient; with HDR, it increased to $6,517; and with EBRT, depending on the number of fractions, the cost varied from $4,173 to $5,507. The total reimbursement for BT was $3,123 versus approximately $8,000 to $10,000 with EBRT. The attending physician time requirement, however, was 1.5 to 2 times greater for BT. The financial incentives relative to time are out of balance.18

Will the ASCENDE-RT lead to changes in this trend? Perhaps. The University of Pittsburgh Medical Center, PA, for example, changed its clinical pathway in January 2016 to indicate EBRT with BB as the first choice approach for high-risk prostate cancer. A retrospective review of patients treated at the hospital between December 2011 and July 2017 showed an increase in patients planned for BB from 25.2 percent to 45.4 percent. The main reason listed for patients not getting a BB was not patient preference (19.9 percent), but rather physician preference (59.7 percent).19

With prostate cancer rates as high as they are, physicians must continue to find ways to improve not just survival, but QOL and financial health as well. As newer technologies have paved the way for earlier detection, better treatment options, and more cures, we also must continue to reduce overtreatment, unnecessary side effects, and avoidable costs. Analysis of the data, cost structures, and the rationale for our current choices will help to guide these efforts moving forward.


References

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  2. Daniyal M, Siddique ZA, Akram M, Asif HM, Sultana S, Khan A. Epidemiology, etiology, diagnosis and treatment of prostate cancer. Asian Pac J Cancer Prev. 2014;15(22):9575-9578.
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  6. National Comprehensive Cancer Network Guidelines for Patients. Prostate cancer. Available at: www.nccn.org/patients/guidelines/prostate/files/assets/common/downloads/files/prostate.pdf. Accessed February 28, 2019.
  7. Jackson MW, Amini A, Jones BL, et al. Prostate brachytherapy, either alone or in combination with external beam radiation is associated with longer overall survival in men with favorable pathologic group 4 (Gleason score 8) prostate cancer. Brachytherapy. 2017;16(4):790-796.
  8. Morris WJ, Tyldesley S, Rodda S, et al. Androgen suppression combined with elective nodal and dose escalated radiation therapy (The ASCENDE-RT trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2017;98(2):275-285.
  9. Rodda S, Morris WJ, Hamm J, Duncan G. ASCENDE-RT: An analysis of health-related quality of life for a randomized trial comparing low-dose-rate brachytherapy boost with dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2017;98(3)581-589.
  10. Demanes DJ, Brandt D, Schour L, Hill DR. Excellent results from high dose rate brachytherapy and external beam for prostate cancer are not improved by androgen deprivation. Am J Clin Oncol. 2009;32(4):342-347.
  11. Lardas LM, Liew M, van der Bergh RC, et al. Quality of life outcomes after primary treatment for clinically localized prostate cancer: A systematic review. Eur Urol. 2017;72(6):869-885.
  12. Chen RC, Basak R, Meyer AM, et al. Association between choice of radical prostatectomy, external beam radiotherapy or active surveillance and patient-reported quality of life among men with localized prostate cancer. JAMA. 2017;317(11):1141-1150.
  13. Wilson LS, Tesoro R, Elkin EP, et al. Cumulative cost pattern comparison of prostate cancer treatments. Cancer. 2007;109(3):518-527.
  14. Martin JM, Handorf EA, Kutikov A, et al. The rise and fall of prostate brachytherapy: Use of brachytherapy for the treatment of localized prostate cancer in the National Cancer Database. Cancer. 2014;120(14):2114-2121.
  15. Glaser SM, Dohopolski MJ, Balasubramani GK, Benoit RM, Smith RP, Beriwal S. Brachytherapy boost for prostate cancer: Trends in care and survival outcomes. Brachytherapy. 2017;16(2):330-341.
  16. Safdieh J, Wong A, Weiner JP, Schwartz D, Schreiber D. Utilization of brachytherapy for low risk prostate cancer: Is the decline overstated? J Contemp Brachytherapy. 2016;8(4):289-293.
  17. Orio PF III, Nguyen PL, Buzurovic I, Cali DW, Chen YW. Prostate brachytherapy case volumes by academic and nonacademic practices: Implications for future residency training. Int J Radiat Oncol Biol Phys. 2016;96(3):624-628.
  18. Dutta SW, Bauer-Nilsen K, Sanders JC, et al. Time-driven activity-based cost comparison of prostate cancer, brachytherapy, and intensity-modulated radiation therapy. Brachytherapy. 2018;17(3):556-563.
  19. Ling DC, Karukonda P, Smith RP, Heron DE, Beriwal S. Declining brachytherapy utilization for high-risk prostate cancer: Can clinical pathways reverse the trend? Brachytherap 2018;17(6):895-898.

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