PCa Commentary #107: Adverse Effects: “Doctor, What Are the Side Effects of Your Treatment?”

Consideration of the adverse effects of different therapies for prostate cancer is integral to an informed decision about what treatment to choose — sometimes the most important issue. It’s basically the question of what am I willing to accept for what I get. This Commentary will address adverse effects associated with radical prostatectomy (RP), intensity modulated radiotherapy (IMRT, a term used to replace EBRT, which may include older techniques), and brachytherapy (BT, i.e., permanent seed implantation). IMRT combined with surgery (as employed in adjuvant or salvage treatment) and the combination of IMRT with BT will be reported. Also to be discussed is CyberKnife (hypofractionated radiation, i.e. 40 Gy delivered over 5 days).

The data has been drawn from a large number of major studies, a few of which will be summarized. A requirement for inclusion was that the data reported be based on patient reported information collated from validated questionnaires. It is acknowledged that patient reported assessments are the only valid way to gain unbiased and accurate information. The extent of functional decline must be adjusted for a man’s condition at baseline and his co-morbidities, which is especially necessary for evaluation of preservation of erectile function where an outcome compressed into a single numerical percentage inadequately accounts for the baseline variation in individual characteristics.

An example of a well-used validated questionnaire is the “Expanded Prostate Cancer Index Composite Index,” which asks about multiple aspects of the major domains of quality of life, i.e., urinary, erectile, and bowel function. Adverse effects are frequently reported as Grades 1 through 5, as in “Common Terminology of Criteria for Adverse Events” (CTCAE) in which Grade 3 is considered “severe or medically significant, but not immediately life threatening.” Grades 1 and 2 are considered “bother” and are temporary.

EXECUTIVE SUMMARY: (1-3 based on Zelefsky, Scardino et al., Sloan Kettering, in Radiation and Oncology, 2016.)

  1. “At 48 months, surgery had significantly higher urinary incontinence than others [IMRT and BT], but fewer urinary irritation/obstructive symptoms,” [i.e. painful urination/difficulty initiating urination].
  2. “Brachytherapy and IMRT showed better sexual function than surgery accounting for baseline function. Sexual bother was similar” [for all three]. … Sexual function was strongly affected in all groups yet significantly less for radiotherapy.”
  3. “Low levels of bowel dysfunction were observed and only small subsets in each group showed rectal bleeding… Using modern radiotherapy delivery, bowel function deterioration is less-often observed.” [The use of a spacer gel to temporarily separate the prostate from the rectum during radiation further reduces rectal injury as does sharper focus of radiation with modern technique, such as CyberKnife therapy.]
  4. Dr. Jaspreet Sandhu, a specialist in reconstructive surgery for voiding dysfunction at Sloan Kettering, confirms this data. “After surgery, the rates of urinary incontinence are on the order of 10% at one year,” [i.e. urinary stress incontinence, or incontinence after activity]. “After radiation therapy for prostate cancer, incontinence rate are actually quite low. On the flip side, you get some elements of obstruction, though the rates are quite low.” Quoted from Prostapedia, October 2016.

Four Studies of Monotherapy and Combined Modality Treatment:

  • ProtecT Trial: “Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer,” NEJM, Sept 2016, Donovan et al.

Incontinence (% use of any pads): at 12 months — RP, 26 % v EBRT, 4%. At 36 months —RP 21% v EBRT, 4%, respectively. By year six 17% in the RP group were using pads versus 4% in the radiotherapy group.

Erectile function (% not firm enough for intercourse); at 12 months — RP, 85% v ERBT, 62%. At 36 months RP, 79% v ERBT, 66%, respectively. At baseline 67% of men reported erections firm enough for intercourse. By year 6 this figure was 17% after RP v 27% after EBRT.

  • Zelefsky et al. (Ibid): “Longitudinal assessment of quality of life [over 48 months] after surgery, conformal brachytherapy, and intensity-modulated radiation therapy for prostate cancer.”

Summary of decline of function between baseline (100 on the scale), and at 48 months:

Incontinence: RP, 95 falling to 82; BT, 96 then 91; and IMRT, 93 then 89.

Irritation or obstruction: RP, 87 improving to 92; BT, 88 then 86; and IMRT, 85 then 84.
[Prostatectomy can address obstruction from BPH and result in improvement.]

Erectile function: RP, 78 reduced to 49; BT, 63 then 50; and IMRT, 56 then 40. Age affects baseline performance. In their study the mean age for RP was 60 years; BT, 67; and IMRT, 70. Understandably, those men with the best baseline function lose the most.

  • Cooperberg, Carroll et al.: UCLA, “Long-term Health-related Quality of Life after Primary Treatment for Localized Prostate Cancer: Results from the CaPSURE Registry,” European Urology, 2015, report comparative toxicity outcomes for prostatectomy, brachytherapy, and external beam radiotherapy.

“Surgery had the largest impact on sexual function and bother and urinary function; radiation had the strongest effect on bowel function ….”

Expressed as clinically meaningful declines from baseline performance they reported outcomes at 2 and 5 years:

Urinary function — The declines for both nerve-sparing and non-NS RP were similar and at 2 years were 54%, and at 5 years 59%; for BT, 40% and 44%; and for EBRT, 24% and 37%.

Sexual function at 2 and 5 years —Nerve-sparing RP, 64% and 62%; non-NS RP, 68% and 67%; BT, 40% and 45%; EBRT, 38% and 41%.

  • Jarosek et al.: University of Minnesota, “Propensity-weighted Long-term Risk of Urinary Adverse Events after Prostate Cancer Surgery, Radiation, or Both,” European Urology, 2015.

This article sets the stage for consideration of a very consequential adverse effect — urethral stricture, that can follow surgery, IMRT, and brachytherapy. However, the message is clear: strictures are significantly increased with combined therapy, i.e. RP combined with IMRT or BT with IMRT. Currently radiation is often used after surgery as immediate or delayed (salvage) treatment at PSA recurrence. IMRT is now regularly combined with a brachytherapy “boost” to achieve optimal outcomes.

The actual incidence of strictures is very difficult to capture because of the complexity of their various causes. A stricture, a scar-like constriction, can occur at any location from the base of the bladder to the tip of the penis. For surgery it usually occurs at the location where the penile urethra is joined to the base of the bladder following the removal of the prostate. A stricture here is termed a bladder neck contraction (BNC). For IMRT or BT, with the prostate remaining in place, scaring can occur from the bladder neck to the base of the penis.

All strictures are not created equal. It is possible to achieve a correction of a surgically caused stricture at the bladder neck with a transurethral surgical repair. Obstruction resulting from radiation induced strictures may require dilation, repeated dilations, or a TURP (transurethral resection), which might help 70% of patients.

Jarosek presented information regarding the occurrence of strictures extracted from a national database based on the registration of hospital procedures. Their total figures included data on naturally occurring strictures. Since the period of their study, 1992 to 2007, techniques in all fields have improved, but the effect of combined therapy is clear: 38.7% for RP+ERBT and 28.4% for BT+ERBT. For monotherapy the incidence is lower: ERBT, 2.8%; BT, 5.2%; and RP, 12.7%.

More current data shows a marked decrease of strictures as presented by Peter Carroll et al. (UCLA), based on the CaPSURE data from urologists at 40 participating institutions. They note that data about BNC can vary from 2.7% to 25.7%! In their analysis stricture rate for RP was 8.4%, RP+EBRT 2.75%; BT, 2.5%; BT+ERBT 5.2%; and for EBRT, 1.7%. When reporting data from their own institutional base of 988 men at UCLA, Carroll et al., BJUI, 2010, cited an incidence of BNC following surgery of 2.2%, indicating the wide variability of this adverse effect and importance of high quality surgical technique.

In the practice of one experienced brachytherapist (personal communication) single dilations for obstruction were reduced to 2.5% and to 0.8% for multiple dilations. The stricture rate reported in the ASCENDE trail which combined IMRT plus a BT boost was 19%, although in this study BT was performed by a variety of physicians.

Measures to lessen this complication for surgery are a skillful use of the robot and excellence in a surgeon’s judgment and technique. Equal excellence is required for brachytherapists for whom the proper placement of seeds is an art form. Quality matters. For radiation therapy there is movement toward restricting the need to augment BT with ERBT and use more sharply focused radiation, such as with CyberKnife, to avoid, where possible, treatment to the base of the bladder.

CYBERKNIFE THERAPY (i.e. extreme hypofractionated radiation)

CyberKnife radiotherapy, sometime termed Stereotactic Body Radiation Therapy (so called because it can be used for cancers other than prostate cancer) is an emerging modality with considerable advantages for the treatment of prostate cancer.  Vol. 97.3 Cyberknife SBRT (control+click link to open or visit www.pctrf.org)

 It delivers intense high-dose radiation in a compressed interval of 5 days (40 Gy in five fractions) as compared to 38 – 39 days of treatment with IMRT. This highly focused radiation can constrain its beams to within 1 mm of the target’s margin as with treatment of the prostate and the seminal vesicles, a capacity that lessen its potential injury to the anterior rectum. Its beam width can be expanded to encompass the periprostatic regions and nearby lymph nodes, as might be indicated for higher-risk cancers. Used this way CyberKnife can be an alternative to brachytherapy plus EBRT.

CyberKnife therapy has been developing over 10 years. Although criticism early-on expressed concern about lack of information about adverse effects, two important recent reviews reported outcomes which allay these fears. To date there have been no randomized comparison with other modalities.

Two Studies:

 ·         Meier et al.  Recently reported in abstract form “Five-Year Outcomes from a Multicenter Trial of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Cancer, Int J Rad Oncol Bio Phys, 2016. The data summarized adverse effects from the treatment of 309 men in 21 community, regional, and academic hospitals. The median follow-up was 61 months. Adverse effects were stratified according to the CTCAE. Grade 1 and 2 urinary toxicity was seen in 53% and 35%, respectively; Grade 3 was 0% at less than 3 months and 2% > 3 months. Grade 1 and 2 gastrointestinal toxicity was seen in 59% and 10%; no Grade 3 adverse effects were seen. 

 ·         Hannah et al., in “Stereotactic body radiation therapy for low and intermediate risk prostate cancer — Results from a multi-institutional clinical trial,” European Journal of Cancer, 2016, reported adverse effects at a median follow-up of 54 months. A variety of doses were used, but the group that most closely resembles the men in the Meier study was the 15 men treated at 45 Gy over five days.  No Grade 3 urinary toxicity occurred before or after 3 months. No Grade 3 bowel toxicity was reported. The next study for this group will use a “biodegradable spacer gel injected between the prostate and the rectum to eliminate all rectal toxicity.”

BOTTOM LINE:  Men are understandably concerned about the loss of urinary and erectile function that can result from treatment. In this Commentary I have not focused on bowel toxicity since it is in that domain that improvement has steadily improved with modern techniques and older data is no longer applicable.  Clear differences among surgery, IMRT, and BT have emerged from these large studies of adverse effects in the domains of urinary and erectile function.

Many practitioners will feel that the published data do not reflect the outcomes experienced in the patients they have treated. In this case the patient must ask for a tally of patient reported outcomes to verify that discrepancy. Individual variation in patient characteristics and physician expertise plague any attempt to generalize. The data presented above is offered as a starting point for discussion.

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