Tissue Preservation May Offer a Harm-Reduction Strategy for Men with Early Prostate Cancer

By: and Mark Embertonlowast

Published online: 01 July 2012

Abstract Full Text Full Text PDF (103 KB)

Refers to article:

Focal Cryotherapy for Clinically Unilateral, Low-Intermediate Risk Prostate Cancer in 73 Men with a Median Follow-Up of 3.7 Years

Duke Bahn, Andre Luis de Castro Abreu, Inderbir S. Gill, Andrew J. Hung, Paul Silverman, Mitchell E. Gross, Gary Lieskovsky and Osamu Ukimura

Accepted 5 March 2012

July 2012 (Vol. 62, Issue 1, pages 55 - 63)

Most men that are diagnosed with early prostate cancer currently receive treatment that targets the prostate, a therapeutic allocation that is independent of risk, tumor volume, or tumor location. The presence of cancer within the prostate and the absence of demonstrable cancer outside the prostate are the only two conditions that need to be satisfied before approaching a man for consent. We should remind ourselves that this is how we used to treat kidney cancer.

This approach to early prostate cancer is becoming increasingly hard to justify given the burden of harm that we currently confer on our patients. This burden really does need to be addressed now we can be fairly sure that the move from open to minimal access prostatectomy has not resulted in the improved functional outcomes we had all hoped for [1]. The results from the Prostate Cancer Intervention Versus Observation Trial were presented at both the American Urological Association annual meeting in 2011 and most recently in Paris at the European Association of Urology 2012 [2]. In summary, the increase in all-cause and prostate cancer–specific survival associated with radical prostatectomy versus conservative management was not statistically significant and no more than 3% in absolute terms. The study has not yet been published, and I am sure that when it is, the design, the conduct, and the results will be hotly debated. What we can say from what we have seen is that the difference in survival between radical therapy and conservative management is, at best, going to be small and will be seen most commonly in men at highest risk.

Such a small survival difference, even if real, may be insufficient to make it worthwhile for the patient, especially if the patient experiences harm. A recent assessment of the trade-off that men were willing to make if they experienced harm after radical prostatectomy shows us just how much these factors have an impact on men's lives. To compensate for the disutility of severe urinary or bowel toxicity that men reported would require at least 2 yr of additional survival [3].

If we can, for a moment, let's agree that in health care only three things really matter: survival, quality of life, and cost of care. In early prostate cancer, which of these presents the greatest challenge to us as urologists? We have enough evidence now that the difference between treatment and no treatment is at best small. We also have evidence that the reduction in the risk of a prostate-related death of 1 in 1000 men screened over an 11-yr period comes at a considerable price and does not affect the overall chance of survival [4].

I would argue that we are left with quality of life and cost. Although both are clearly important and linked (poor life quality often results in additional and recurrent costs to the health care provider), it is quality of life I would currently prioritize. If the opportunity for benefit is small, so too must be the harms that come with the treatment.

This leads me to the article by Dr. Bahn and colleagues published in this issue of the journal [5]. Here we have a report generated by a group of clinicians who have sought to address the issue of quality of life for men undergoing treatment for prostate cancer by modifying their method of assessment and therapy to confer to their patients a virtual guarantee of pad-free continence (100% in this series) and a 7 in 10 chance of reporting erections sufficient for penetration at 1 yr.

They did this by expending additional effort in their assessment of men by incorporating an image-guided biopsy technique (incorporating both gray scale and color Doppler) and then directing their therapy at the lobe of the prostate with the dominant disease. The benefit, in terms of function, we must assume comes from shielding prostate tissue from the effects of therapy.

Two things are worth emphasizing. The first is that the use of strategies other than or in addition to random sampling (standard transrectal ultrasound biopsy) of the prostate will confer a higher yield of clinically significant disease and reduce the false-negative rate for this type of prostate cancer [6]. Although an ultrasound of a so-called lesion was not a perfect predictor of clinically significant disease, its presence was associated with “clinical significance” by virtue of greater cancer core lengths (6mm vs 1mm) and the more likely presence of a Gleason pattern 4 (66% vs 25%) when targeted by biopsy. Conversely, absence of an echo-poor lesion was associated with a reasonable likelihood of either no disease or clinically insignificant disease. These improvements in both positive predictive value and negative predictive value for clinically significant disease gave the investigators the confidence to offer these patients a selective form of therapy.

The ability of the investigators to rule out clinically significant disease in the untreated lobe appears vindicated. Only 3 of the 48 men agreeing to biopsy over the period of the study proved to have anything we might wish to call significant (presence of Gleason pattern 4 and/or a maximum cancer core length ≥5mm of any grade) [7]. Therefore, in the untreated lobe the rate of progression/reclassification was much less that we would see in a typical active surveillance cohort.

What about the treatment? How effective was it at rendering the men free from clinically significant disease in the treated lobe? In this regard we are fortunate because the investigators set a high ceiling in terms of risk. Most of the men had Gleason pattern 4, and in a quarter of them it was in its dominant form. One in 10 men had a prostate-specific antigen (PSA) between 10 and 20μg/l. Only one patient had residual/recurrent disease in the treated lobe, although not all men were biopsied. I am not too concerned about this for two reasons. First, you cannot force a man to have a biopsy. Even in protocol-driven studies, the response to this kind of invitation is often a polite “no.” And second, there was little to suggest that the men who decided to forgo biopsy were at any greater risk than those who did. Indeed their PSAs were both lower and more stable.

What judgments can we make? This group of investigators in this group of patients managed to achieve good early oncologic control in a group of patients who would otherwise have had radical whole gland therapy and who would almost certainly have experienced greater harm. The intervention appears safe and was very well tolerated.

I see three main problems. The first relates to reproducibility. One should not underestimate the skill that this group of investigators has acquired. Targeted biopsy is a high-level competency, not widely held and not currently taught to our trainees. In addition, the ability to control an ice ball in one lobe of the prostate with sufficient precision to avoid harm is, once again, not easy.

The second relates to the burden placed on the patient in terms of repeat biopsy, both for treatment verification and for surveillance of the preserved tissue. This needs to be addressed if tissue preservation is to flourish as a strategy.

The authors are confident that technology will come to our rescue. Improvements in magnetic resonance imaging, coupled with an image-directed biopsy using an image-to-image registration system, seems to be the direction of travel [8]. The same imaging appears both sensitive and specific for recurrence in the treated gland after focal ablation [9]. In focal therapy as in active surveillance it is likely the imaging will slowly replace the biopsy as our indicator of disease stability.

The third relates to the forward accumulation of evidence. Clinical, conceptual, and technical advances are progressing at a rate much faster than was previously the case. Traditional fixed head-to-head trials are unlikely to remain sufficiently fresh to inform practice by the time they are ready to report. Randomization is also going to prove a challenge, particularly when the functional outcomes differ significantly between therapies. Quick, innovative, pragmatic, adaptive, and comparative study designs are going to be necessary if we are to generate the kind of information that will be useful to patients who are facing the challenging decision of what treatment to have.

Conflicts of interest

Mark Emberton receives research support from the United Kingdom's National Institute of Health Research UCLH/UCL Comprehensive Biomedical Research Centre, London, UK. He has been an investigator, speaker bureau participant, and consultant for GSK Pharma, Sanofi Aventis Pharma, STEBA Biotech, and USHIFU; an investigator for Advanced Medical Diagnostics; a consultant for Jensen Pharma; and a speaker bureau participant for Astra Zeneca. He is a director of Mediwatch PLC and Prostate Mapping Ltd and a founding partner of London Urology Associates.


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