A widely used nomogram for clinical decision making about salvage radiation therapy (SRT) after radical prostatectomy (RP) has been updated and was published online August 15 in the Journal of Clinical Oncology.
Changes to the Stephenson nomogram indicate that SRT initiated at any detectable PSA level may be associated with significantly improved outcomes of freedom from biochemical failure and distant metastases.
Previously, the tool had indicated that an increase in prostate-specific antigen (PSA) greater than 0.2 ng/mL warranted initiation of SRT.
"There have been significant changes in the way we manage patients with rising PSA following RP. We have seen referrals for considering SRT at PSA levels lower than 0.2 ng/mL with ultrasensitive PSA assays. Microscopic disease can now be detected early, and that is why we embarked on this project," said lead author Rahul D. Tendulkar, MD, a radiation oncologist at the Cleveland Clinic in Ohio.
"Our study shows that the earlier SRT is initiated, the odds of a successful cure are higher," he told Medscape Medical News.
The prostate cancer population continues to change, and so must the tools for evaluating it, said Paul L. Nguyen, MD, a radiation oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts.
The number of men with pathologic T3 or margin-positive prostate cancer seeking radical prostatectomy is increasing, says Dr Nguyen, author of an editorial accompanyingthe new study of the nomogram.
The scope of the new paper is outstanding, he notes. "The authors impressively combined nearly 2,500 patients who received salvage radiation at 10 different academic institutions to form a data set that is surely greater than the sum of its parts."
Both Dr Tendulkar and Dr Nguyen note that this is the first nomogram to report on the endpoint of distant metastases — which is of greater clinical relevance and significance for physicians and patients compared with biochemical recurrence.
"For practicing physicians, the key message that should emerge from this work is the importance of initiating salvage radiation as early as possible while the PSA is still low to minimize the risk of distant metastases," Dr Nguyen writes.
Dr Tendulkar pointed out that, with almost double the number of patients compared with those used to generate the Stephenson nomogram, this is the largest case series of SRT outcomes in the literature and includes patients with PSA levels lower than 0.2 ng/mL
The updated nomogram includes other predictive factors, such as surgical Gleason scores, extraprostatic extension, surgical margins, RT dose to the prostate bed, and concurrent androgen deprivation therapy (ADT). However, the most significant update has been with respect to redefining when SRT should be undertaken for rising PSA after RP — at the earliest time that a rising PSA is observed, even as low as 0.1 ng/mL in higher-risk patients.
A Contemporary Multi-Institution Predictive Nomogram
To construct the nomogram, 10 academic institutions provided data for 2460 patients (1987 to 2013) who underwent open or laparoscopic RP and were treated with SRT for a detectable PSA based on the assay used at the treating institution.
Patients were excluded if they received adjuvant RT, ADT was instituted before RP or more than 6 months before SRT, had histologically positive lymph nodes, or had unavailable information on pathologic staging or follow-up.
Clinical management decisions were at the discretion of the treating physicians at high-volume, tertiary referral centers specializing in treating genitourinary cancers.
Biochemical failure was defined as "serum PSA rising above the post-treatment nadir to a level of 0.2 ng/mL or more with a confirmatory value or by the initiation of salvage ADT after completion of SRT."
Rates of biochemical failure and distant metastases were estimated by cumulative incidence using univariate and multivariate models.
Results
The median age of patients was 64 years; the median age at surgery was 61 years. The median time from RP to SRT was 25 months.
Table. Baseline Patient Information
| Patient Characteristic | Value (%) |
| Gleason score (grade group) | |
| ≤6 | 24 |
| 7 (2 - 3) | 56 |
| 8 (4) | 10 |
| 9 - 10 (5) | 9 |
| Median pre-SRT PSA | |
| 0.01 - 0.2 ng/mL | 18 |
| 0.21 - 0.5 ng/mL | 33 |
| 0.51 - 1.0 ng/mL | 22 |
| 0.01 - 2.0 ng/mL | 14 |
| >2.0 ng/mL | 13 |
| Extraprostatic extension | 56 |
| Seminal vesicle invasion | |
| Yes | 18 |
| No | 84 |
| Surgical margins | |
| Positive | 58 |
| Negative | 40 |
| Unknown | 2 |
| ADT | |
| Yes | 16 |
| No | 84 |
| Median radiation dose | |
| <66 gy="" td=""> | 47 |
| ≥66 Gy | 53 |
| Radiation fields | |
| Prostate bed only | 83 |
| Pelvic nodal radiation | 17 |
The 5-year rate of freedom from biochemical failure was 56% for all patients and decreased with increasing pre-SRT PSA levels: 71% for the lowest level (0.01 to 0.2 ng/mL) and 37% for the highest level (>2.0 ng/mL).
For distant metastases, the 10-year cumulate rate was 19% for all patients and increased with increase PSA levels: 9% for the lowest level (0.01 to 0.2 ng/mL) and 37% for the highest level (>2.0 ng/mL).
These data were all statistically significant (P < .001). The authors provide a predictive nomogram, which calculates a point estimate for each factor. Addition of all the points provides a total score, which is used to estimate the risk for biochemical recurrence. An online version of the calculator is available here.
What Is Explained and What Is Not
Dr Tendulkar said that the American Society for Radiation Oncology and the American Urological Association provided consensus guidelines in 2013 that postoperative RT "should be administered at the earliest sign of PSA recurrence." These recommendations followed on the heels of the publication of three randomized studies, which showed that adjuvant RT after RP was associated with significant clinical benefits compared with observation alone. However, the threshold of PSA was not defined.
"Now we have shown that the SRT can be initiated at pre-SRT PSA as low as 0.1 ng/mL," Dr Tendulkar pointed out.
"In contemporary practice, it is not uncommon for clinicians to wait until the PSA reaches 0.3 or 0.4 ng/mL or even higher before recommending salvage radiation therapy," Dr Nguyen writes.
"What [this study shows] is that we may be doing our patients a disservice if we still consider salvage radiation initiated at a PSA of < 0.5 ng/mL to be early," he adds.
According to Dr Nguyen, SRT should typically begin when PSA levels reach 0.2 ng/mL, and lower for higher-risk patients. To those who believe that this will lead to overtreating some patients, he put forward the concept of risk-adapted thresholds. "The concept relates to the fact that for any given ultrasensitive PSA level, higher-risk patients are more likely to subsequently experience true failure than lower-risk patients; therefore, their PSA threshold for predicting failure can also be lower," he states.
He explained that for a low-risk patient, risk for distant metastases at 10 years will be greater than 3%, no matter if SRT is initiated at a PSA of 0.1 or 0.5 ng/mL. "But for a patient with pT3b, Gleason 9, and margin-negative disease, a 30% chance of metastasis if the salvage radiation is started when the PSA is 0.1 ng/mL would grow to about 45% if the PSA were allowed to drift up to 0.5 mg/mL," he writes.
Dr Tendulkar stressed that the study was not meant to determine whether adjuvant RT was preferred to SRT given at the first sign of postprostatectomy PSA elevations. "The RAVES and RADICAL studies, which are ongoing, will provide insights into that question," he said.
The study investigators note several limitations. Patients were treated at institutions during a 25-year span in which treatment techniques and PSA assay methods evolved over time. In addition, high-grade tumors represented only a fifth of all patients, "limiting the broad applicability of the study findings." Finally, with the use of ADT varying widely, the optimal integration of ADT into SRT was also not possible, they note.
Although the study investigators observe that they could not address the common practice of delaying radiation so that patients can recovery from urinary incontinence or sexual dysfunction after surgery, Dr Nguyen was more emphatic that SRT should not be delayed for this reason. "[B]ecause most patients contemplating salvage radiation have already healed fully from their surgery, from a functional perspective, there is little to be gained in further delaying radiation therapy and potentially a great deal to lose," he writes.
In addition, Dr Nguyen notes that even in light of these findings, institution of SRT at the earliest detection of rising PSA is not for all patients. Especially in older patients who are at a lower risk for prostate-cancer mortality compared with noncancer mortality, "continued observation and avoidance of the non-negligible toxicity of salvage radiation would be reasonable," he says.
The study investigators agree. "Ultimately, the postoperative management of men with adverse pathologic features and/or a detectable PSA after RP must take into account several issues, including life expectancy, quality of life, and the likelihood of tumor control," they conclude.
Several authors linked with the publication have disclosed financial relationships with industry. Dr Tendulkar has disclosed no relevant financial relationships. Dr Nguyen reported having a financial relationship with Medivation, GenomeDx, and Ferring.
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