Better defining appropriate candidates for active surveillance ...

A forthcoming paper from Tewari?s group at Weill Cornell Medical College in New York describes a new set of nomograms for assessment of risk for worsening prognosis in men with localized prostate cancer who might otherwise be considered appropriate candidates for management under active surveillance.

Sooriakumaran et al. based their study on data from a cohort of 2,476 patients, all treated by robot-assisted laparoscopic prostatectomy (RALP) between January 2005 and September 2010. Of these 2,476 patients, 750 met reasonably well-established (?standard?) criteria suggesting that they would be eligible for management under active surveillance (a PSA level ? 10 ng/ml; clinical stage of ? cT2a; a Gleason score of ? 6; not more than two positive cores on biopsy; and not more than 50 percent of any individual biopsy core being positive for cancer). However, these patients were not ever given the repeat biopsy that is considered advisable by several leading centers prior to entry into an active surveillance protocol. Although all biopsy specimens were centrally reviewed at Weill Cornell prior to RALP, not all of the original biopsies had been carried out at this institution, and many patients were in fact treated there after prior biopsy at community-based urology practices and other centers. Pathologic examination and centralized review of all the post-surgical prostate specimens was conducted at Weill Cornell.

What the authors did then was to compare the post-surgical pathology findings to the biopsy pathology findings to clarify just what proportion of the 750 patients really were good candidates for active surveillance at the time of surgery, and to use these data to develop predictive nomograms that could help to better identify these patients. So ? here are the initial findings:

• 297/750 patients (39.6 percent) in the eligible study cohort actually had a post-surgical Gleason score > 6.
• 29/750 patients (3.9 percent) in the eligible study cohort actually had a pathologic stage of at least pT3a.
• 303/750 patients (40.4 percent) in the eligible study cohort were either upgraded and/or upstaged and were therefore not actually eligible for active surveillance at the time of surgery.
• Patients found to be upgraded at post-surgical pathology shared a number of pre-surgical characteristics compared to those who were not upgraded.
• They had significantly higher body mass indices (BMIs) (p = 0.04).
• They had significantly higher preoperative PSA levels (p < 0.001).
• They had higher numbers of positive biopsy cores.
• They had higher maximum amounts of cancer in their biopsy cores.
• Within the total eligible study cohort, there were no significant differences between the 303 patients who were upgraded and/or upstaged and the 447 who were not with respect to
• Patient age
• Numbers of biopsy cores taken at biopsy
• Presence of high-grade PIN on biopsy
• Pre-surgical Gleason score
• Pre-surgical clinical stage

The authors go on to describe the development of three nomograms that can be used to estimate:

• The probability of a patient being upgraded at the time of surgery (based on the preoperative PSA level, whether one or two cores was positive for cancer, and on the patient?s prostate volume)
• The probability of a patinet being upstaged at the time of surgery (based on the preoperative PSA level, whether one or two cores was positive for cancer, and on the patient?s prostate volume, and the pre-surgical clinical stage )
• The probability of a patient having a worsening prognosis if managed by active surveillance (again based on the preoperative PSA level, whether one or two cores was positive for cancer, and on the patient?s prostate volume)

Many in the urology community are concerned that patients with clinical evidence of low-risk disease who are managed with active surveillance may actually be at significant risk for progressive disease and that active surveillance for even a brief time period may permit disease progress to an incurable state. (The advocates for active surveillance would likely state, however, that the data now available do not generally support this concern.) The ability to project, with a high degree of accuracy, which patients who appear to be suitable candidates for active surveillance are actually not good candidates for management by monitoring in this manner is certainly critically important. However, The ?New? Prostate Cancer InfoLink is concerned that the nomograms proposed by Sooriakumaran et al. may have a number of significant and inbuilt flaws, as follows:

• First, since leading centers currently propose that patients being considered for active surveillance should be rebiopsied prior to entry into a study protocol, it seems to us that any nomogram of this type should be built on the basis of patients who have in fact been rebiopsied (or at least biopsied) according to a reasonably standardized protocol.
• Second, the average age of the patients in this study cohort seems low (at about 58 to 60 years), which means they have average life expectancies of 20 or so years. Are these really typical candidates for active surveillance or are these data affected by a high rate of referrals of younger men for RALP at a widely recognized center specializing in this type of surgery? (Unfortunately, the age range of the patients is not available in the actual article.)
• Third, the rate of upstaging and upgrading reported in this study seems relatively high at 40.4 percent compared to that supposedly being achieved today at other major academic centers.

The authors have commented on some of these issues in the Discussion section of their paper. They have also carefully noted that their nomograms have yet to be validated through the use of data from independent centers to see if it accurately predicts which patients are at risk for upgrading and upstaging based on another data set.

What this study definitely does do is offer a sound preliminary model, based on a large data set, for the development of predictive nomograms that can help the practicing clinician and his or her patients to assess the long-term risks and benefits of active surveillance as a management strategy ? most particularly for those patients with a reasonable life expectancy of up to about 15 years. However, we really wonder whether better nomograms could potentially be developed based on data from the 10-year follow-up of cohorts of patients who have actually been enrolled in long-term active surveillance studies.

There are three critical issues regarding the value of nomograms (or other predictive tools) in expanding appropriate use of active surveillance, in our minds:

• We clearly need to be able to accurately identify those patients whose potential pathologic status is likely not conducive to active surveillance even though their clinical status suggests they are appropriate candidates. We believe that a repeat biopsy prior to initiation of active surveillance may well be an essential component of the evaluation of such patients.
• We need to be able to accurately identify the real need for repeat biopsies in men actually on active surveillance protocols, since every biopsy comes with risks for complications, and an excessive number of biopsies over time could, in and of itself, induce real long-term side effects.
• We need to be very careful to ensure that the reasonable, normal life expectancy of the patient is taken into account in making decisions about the application of active surveillance. The application of active surveillance to a man in his late 40s may be conducted for quite different reasons to those for application of the same management strategy in a man with the same clinical characteristics who is in his mid to late 70s.

We would like to thank Drs. Tewari and Sooriakumaran for providing us with the full text of their paper (to be published in International Urology and Nephrology) and for clarifying certain technical questions about the content of that paper.

Filed under: Diagnosis, Management, Risk Tagged: | active surveillance, candidate, nomogram, prognosis, risk

Source: http://prostatecancerinfolink.net/2011/07/22/better-defining-appropriate-candidates-for-active-surveillance/

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