Pacjenci wysokiego ryzyka. Kiedy RT po RP w epoce uPSA?

Pacjenci wysokiego ryzyka. Kiedy RT po RP w epoce uPSA?

Nieprzeczytany postautor: zosia bluszcz » 04 lis 2018, 08:54

Ultraczule testy PSA (uPSA) po RP pomagają skutecznie identyfikowac pacjentow wysokiego ryzyka wymagających pooperacyjnej radioterapii.
(Publikacja z 2015 roku autorstwa specjalistow z UCLA School of Medicine.)

Pacjenci wysokiego ryzyka - w histopatologii pooperacyjnej przekroczenie torebki, zajęcie pecherzykow nasiennych i/lub dodatni margines chirurgiczny)
Wg autorow uPSA ≥0.03 ng/ml stanowi prog, przy ktorym nalezy wprowadzic pooperacyjną RT jesli ma ona zakonczyc się sukcesem.
Pacjenci wysokiego ryzyka, powinni badac PSA co 6 miesięcy przez okres min. 5 lat. Jesli w tym czasie uPSA osiągnie poziom ≥0.03 ng/ml bedzie to oznaczalo biochemiczną wznowe (cBCR) i koniecznosc poddania sie RT w celu skutecznego wyeliminowania raka.
Oczekiwanie na poziom PSA 0.2 ng/ml jest w epoce uPSA anachronizmem i zmniejsza szanse na skuteczną RT.

Ultra-sensitive PSA Following Prostatectomy Reliably Identifies Patients Requiring Post-Op Radiotherapy
Jung Julie Kang, MD, PhD1, Robert Reiter, MD2, Michael Steinberg, MD1, and Christopher
R. King, PhD, MD1
1Department of Radiation Oncology, UCLA School of Medicine, Los Angeles, CA
2Department of Urology, UCLA School of Medicine, Los Angeles, CA


Integrating ultra-sensitive PSA (uPSA) into surveillance of high-risk patients following radical prostatectomy (RP) potentially optimizes management by correctly identifying actual recurrences, promoting an early salvage strategy and minimizing overtreatment. The power of uPSA following surgery to identify eventual biochemical failures is tested.

From 1991–2013, 247 high-risk patients with a median follow-up was 44 months after RP were identified (extraprostatic extension and/or positive margin). Surgical technique, initial PSA (iPSA), pathology and post-op PSA were analyzed. The uPSA assay threshold was 0.01 ng/mL.
Conventional biochemical relapse (cBCR) was defined as PSA ≥0.2 ng/mL.
Kaplan Meier and Cox multivariate analyses (MVA) compared uPSA recurrence vs. cBCR rates.

Sensitivity analysis identified uPSA ≥0.03 as the optimal threshold identifying recurrence.
First post-op uPSA ≥0.03, Gleason grade, T-stage, iPSA, and margin status predicted cBCR.
On MVA, only first post-op uPSA ≥0.03, Gleason grade, and T-stage independently predicted cBCR.
First post-op uPSA ≥0.03 conferred the highest risk (HR 8.5, p<0.0001) and discerned cBCR with greater sensitivity than undetectable first conventional PSA (70% vs. 46%).
Any post-op PSA ≥0.03 captured all failures missed by first post-op value (100% sensitivity) with accuracy (96% specificity).
Defining failure at uPSA ≥0.03 yielded a median lead-time advantage of 18 months (mean 24 months) over the conventional PSA ≥0.2 definition.

uPSA ≥0.03 is an independent factor, identifies BCR more accurately than any traditional risk factors, and confers a significant lead-time advantage. uPSA enables critical decisions regarding timing and indication for post-op RT among high-risk patients following RP.

In the present study, we analyzed the use of postoperative uPSA to detect recurrence among patients at high-risk after radical prostatectomy who would otherwise be eligible for adjuvant RT.

Our data yielded three primary conclusions when using a uPSA relapse criterion of ≥0.03 ng/mL at any time following RP:
1) it reliably identified all eventual relapses with high sensitivity (100%) and specificity (96%),
2) it was independent when compared to any of the conventional factors (HR 8.5, p<0.0001), and
3) it provided a median 18 months lead-time advantage over the conventional relapse criteria.

These findings translate into a clinical management pathway for high-risk prostatectomy patients. Specifically, initial and continual monitoring with uPSA out to at least 5 years and at intervals not longer than 6 months between tests so that eventual failures can be identified earlier and postop RT can be initiated with a greater likelihood of success.

A few studies have used uPSA to risk-stratify or model failures, for example patients with undetectable uPSA at 2 to 3 years after prostatectomy are classified as less likely to fail [11,12].
The most advanced uPSA assays detect values at the pg/mL level (1 picogram, pg = 0.001 nanogram, ng) but come at the cost of false positives.
The capacity to measure such low values may not be necessary or valuable, as it is known that serum PSA levels ≤30 pg/mL can be produced by nonmalignant sources of PSA [13], from benign cells left at the bladder neck, urethral margin, or periurethral glands [14–19].

Furthermore, the reported analytical sensitivity of a lab assay may differ from its ‘real-life’ diagnostic sensitivity, which is confounded by specimen sampling, processing, and interfering factors in human serum [20].
Residual cancer cells at positive surgical margins or micro-metastatic disease usually produce measurable amounts of PSA, although very rarely some high-grade and undifferentiated tumors may not produce PSA at all [21–23].

Depending on what ultrasensitive value is considered to be ‘detectable,’ the pattern over time is critical to contextualize any single measurement.
These issues have contributed to the challenge of routine clinical implementation of uPSA.

Although the optimal use of uPSA has not yet been categorically established, use of the conventional assay and cutoff (PSA ≥0.2 ng/mL) is flawed.
Patients with an ‘undetectable’ PSA (<0.2 ng/mL) may actually be failing, as one study showed that 23% ultimately relapsed biochemically after five years [7].
With the uPSA assay, this gradual process of BCR can be recognized much sooner.

Our data showed that about half of relapses missed by conventional PSA relapse criteria would be anticipated with uPSA. The majority of our patients had uPSA failures within the first three years (82%) but a substantial number (18%) relapsed much later and therefore a closer PSA surveillance probably should extend to a minimum of 5 years.

The clinical relevance of uPSA-based early identification of recurrence lies in its direct relationship to the success of post-op radiotherapy (RT).
Radiotherapy has the potential to eradicate microscopic residual disease and cure local recurrence.
Currently, patient selection for adjuvant radiotherapy (ART) is based upon high-risk pathologic features (extracapsular extension, seminal vesicle invasion and/or positive surgical margins).

Three randomized trials showed improved biochemical relapse-free survival with ART when compared to observation: the EORTC trial [24], the SWOG trial [25] and the ARO trial [26].

The SWOG showed that improved BCR-free survival translated into overall survival and distant metastatic-free survival advantages [27].
While these trials demonstrated the unequivocal benefit of post-op RT as compared with observation, these studies did not answer the fundamental question of ART vs. early SRT, but merely that ART is better than delayed SRT, ADT alone, or neither.

Three randomized trials are underway to answer the question of ART vs. early SRT:
Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS, MRC-UK) [28],
Radiotherapy Adjunct vs. Early Salvage (RAVES, TROG) [29], and
Groupe d’Etude des Tumeurs Uro-Genital (GETUG-17) [30].

These trials will evaluate how immediate post-op RT for high-risk pathology in the setting of an undetectable PSA compares with early salvage RT at the first indication of PSA recurrence (set as >0.1 ng/mL [28] or PSA >0.2 ng/mL [29, 30]).

It is well established from numerous retrospective series and a recent pooled analysis [9] that SRT is more effective when initiated at lower PSA values. A meta-analysis quantified the success of salvage RT to decrease by 2.5% with every 0.1 PSA increment [10]. Even patients with high-risk pathology benefit from post-op RT at lower PSA values, as shown by two separate matched-pair analysis studies [31–32], as well as within the EORTC and SWOG ART trials. Collectively, all of this evidence confirms that improved outcomes are achieved when post-op RT is delivered at lower PSA entry levels.
While the ‘ideal’ definition of BCR is a testable hypothesis, there can be little doubt that the utility of uPSA assays will be entirely lost if recurrence remains defined as a post-op PSA >0.2 ng/mL.
Ultimately, whether a lead-time and earlier initiation of salvage RT translates to improved metastasis-free and overall survival needs to be tested with a randomized prospective trial.

Ultra-sensitive PSA Following Prostatectomy Reliably Identifies Patients Requiring Post-Op Radiotherapy.pdf
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