Posted 7/23/2017 1:25 PM (GMT -7)
We reviewed his MRI with him, which was negative for any evidence of local recurrence such as nodules or
enhancement. Moreover, his PSA today was 0.12, which is essentially stable from his previous measurement a
#1 Prostate cancer status post radical prostatectomy, pT3b, N0, Gleason 4 + 5 = 9, surgical margins negative
We emphasized that his current level of detectable PSA does not meet the formal definition for
biochemical recurrence. We reviewed the differential which may include benign glands versus recurrent
prostate cancer, which in turn may either be localized to the prostatic bed or distant. It is encouraging
that the PSA has demonstrated stability over a month's time.
We reviewed the options of ongoing PSA monitoring, with the next measurement in three months, versus
Radiation Oncology consultation for adjuvant radiotherapy. The pros and cons of each approach was
reviewed in detail. He opted to proceed with ongoing PSA surveillance.
We therefore booked a clinic visit with a repeat PSA in three months' time. We also provided him with
our card, should he want us to facilitate a referral to a radiation oncologist.
Predicting the Outcome of Salvage Radiation Therapy for Recurrent Prostate Cancer After Radical Prostatectomy
Andrew J. Stephenson
, Peter T. Scardino
, Michael W. Kattan
, Thomas M. Pisansky
, Kevin M. Slawin
, Eric A. Klein
ChooseTop of pageAbstract <<INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAUTHORS' DISCLOSURES OF P...AUTHOR CONTRIBUTIONSREFERENCESCITING ARTICLES
An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence.
Patients and Methods
Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients.
The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69.
Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.
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An estimated 25% of patients treated with radical prostatectomy (RP) for clinically localized prostate cancer will suffer recurrence of their disease, manifested initially as a rising serum prostate-specific antigen (PSA) level with no radiographic evidence of cancer.1 In the absence of salvage therapy, the median time from PSA recurrence to distant metastasis is 8 years.2
A critical issue in the management of these patients is determining whether a rising PSA reflects local or distant recurrence, as the former may potentially be cured by salvage radiation therapy (SRT). Androgen-deprivation therapy (ADT) appears only to offer palliation for those patients with recurrent prostate cancer. For the best chance of success, SRT to the local tumor bed must be administered when the cancer burden is lowest; that is, when the serum PSA first reaches detectable levels.3-15 At these PSA levels, neither imaging studies nor anastomotic biopsy are sufficiently sensitive or specific enough to distinguish those with local recurrence who are suitable for SRT from those with disseminated disease who require systemic therapy.16-19 As a consequence, the reported success rate of SRT after RP has been poor, ranging from 10% to 40%.4,7,8,12,13,15,20,21
PSA recurrence associated with a rapidly rising PSA (quantified by a short PSA doubling time [PSADT]), poorly differentiated cancer (Gleason grade 8 to 10), and a short disease-free interval after RP identifies patients at the highest risk for progression to distant metastasis and cancer-specific mortality who are in the greatest need of effective salvage therapy.2,22,23 PSA recurrence associated with these features is widely believed to represent occult metastatic disease. Hence, most high-risk patients with a rising PSA are treated with early ADT despite the lack of conclusive evidence that that it prolongs survival,24 and the potential for long-term toxicity and adverse effects on quality of life.25,26 However, a recent retrospective study demonstrated that a substantial proportion of recurrent patients with a short PSADT and/or Gleason grade 8 to 10 cancer were cancer free at 4 years after SRT alone,13 but this favorable outcome was dependent on several disease parameters.
Because of the inadequacies of current diagnostic modalities for selecting patients for SRT and the variable outcome depending on patient parameters, models that accurately predict the outcome of SRT on the basis of the overall characteristics of an individual's case rather than a single parameter (eg, PSADT) are needed to select patients for this therapy. We present a predictive model called a nomogram that predicts the 6-year progression-free probability after SRT for men with PSA recurrence after RP.
PATIENTS AND METHODS
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For the purpose of developing predictive models for the outcome of SRT, a multi-institutional, retrospective cohort of 1,603 consecutive patients from 17 North American tertiary referral centers who received SRT after RP for PSA recurrence between 1987 and 2005 was assembled. Before SRT, all patients had a PSA level of 0.2 ng/mL or higher at least 6 weeks after RP followed by another higher value, or a single PSA of 0.5 ng/mL or higher.27 Sixty-three patients (4%) received adjuvant ADT after SRT and were excluded from the analysis of PSA-defined end points, leaving 1,540 patients for nomogram development and validation (Table 1). With the exception of a higher positive surgical margin rate and lower rates of seminal vesicle invasion and lymph node metastasis, the clinical characteristics of this cohort were similar to those of consecutive patients with PSA recurrence in RP series.2,28
Because some patients underwent RP at an outside institution, the method by which the pathologic specimens were processed was not available for all patients. PSADT was calculated using previously described methods based on a minimum of two PSA values at least 6 weeks apart.2 Two hundred fourteen patients (14%) received ADT before and/or during SRT for a median duration of 4.1 month (range, 1 to 24 months); 25% of these patients received ADT for longer than 6 months.
After radiation treatment, patients were followed with clinical assessment and serum PSA determinations at regular intervals. The use of diagnostic imaging studies and salvage ADT was not standardized, and varied over time and by individual physician practice. The median follow-up after the completion of SRT was 53 months (interquartile range, 28 to 81 months).
The primary end point of this study was disease progression after SRT, defined as a serum PSA value of 0.2 ng/mL or more above the postradiotherapy nadir followed by another higher value, a continued rise in the serum PSA despite SRT, initiation of systemic therapy after completion of SRT, or clinical progression. Progression-free probability was estimated using the Kaplan-Meier method, and survival was calculated from the completion date of radiotherapy with no back-dating of recurrence. Multivariable Cox proportional hazards regression analysis was the basis for the nomogram. Variables to be used in the nomogram were selected on the basis of knowledge of their prognostic significance from previous reports. All decisions with respect to the categorization of variables were made before modeling. Because of skewed distributions, continuous variables were modeled using restricted cubic splines to accommodate potentially nonlinear effects.
Internal validation of the nomogram was performed using two components. First, a concordance index (c-index), which is similar to an area under the receiver operating characteristic curve, was estimated by subjecting the nomogram to bootstrapping with 200 resamples to calculate an unbiased measure of its ability to discriminate among patients.29,30 The c-index is the probability that, given two randomly drawn patients, the patient who relapses first had a higher probability of recurrence. With this measure, a c-index of 1.0 represents a perfectly discriminating model, and a value of 0.5 is that expected by random chance. The second component of validation compared the predicted probability of disease recurrence versus actual recurrence (ie, nomogram calibration) of the 1,540 patients using 200 bootstrap resamples to reduce overfit bias, which would overstate the accuracy of the nomogram.
All statistical analyses were conducted using S-Plus 2000 Professional statistical software (Insightful Corp, Seattle, WA) with the Design library attached.31 All P values resulted from the use of two-sided statistical tests, and the level of significance was set at .05. The study was conducted under Health Insurance Portability and Accountability Act guidelines and received institutional review board approval from all participating institutions.
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Overall, 866 patients experienced disease progression after SRT, and the 6-year progression-free probability was 32% (95% CI, 28% to 35%; Fig 1A). However, an estimated 48% (95% CI, 40% to 56%) who received SRT alone without ADT when the PSA was 0.50 ng/mL or less were disease free at 6 years compared with 40% (95% CI, 34% to 46%), 28% (95% CI, 20% to 35%), and 18% (95%, 14% to 22%) of those treated at PSA levels of 0.51 to 1.00, 1.01 to 1.50, and greater than 1.50 ng/mL, respectively (Fig 1B). The 6-year response to SRT among patients treated at PSA levels of 0.50 ng/mL or less appears to be durable because only two progression events were observed after 6 years among 32 patients at risk at 6 years (median follow-up, 90 months).
Sufficient data to evaluate the PSA response to SRT was available for 1,491 patients (97%). A PSA nadir after radiotherapy of 0.10 ng/mL or less was achieved in 905 patients (59%), including 726 (55%) of 1,326 patients who did not receive ADT.
We previously reported favorable 4-year response rates after SRT alone in 356 patients with a short PSADT and Gleason grade 8 to 10 cancer.13 In this larger cohort with longer follow-up, the 4-year progression-free probability estimates after SRT alone stratified by PSA before SRT (cut point, 2.0 ng/mL), Gleason grade 7 or less surgical versus 8 to 10, surgical margins, and PSADT (cut point, 10 months) were generally within 10% of those previously reported, validating the favorable intermediate prognosis in select high-risk patients (Fig 2). When SRT was administered at PSA levels of 0.50 ng/mL or less, an estimated 41% (95% CI, 31% to 51%) of patients with a PSADT of 10 months or less or Gleason grade 8 to 10 cancer were disease free at 6 years, including 48% (95% CI, 35% to 62%) who also had positive surgical margins.
A nomogram predicting the 6-year progression-free probability after SRT was constructed from 11 parameters determined before treatment (Fig 3A). Statistically significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSADT (P < .001), surgical margins (P < .001), ADT administered before or during SRT (P < .001), and lymph node metastasis (P = .019). Statistically insignificant variables were not omitted from the model because of the resultant bias on the remaining predictors and subsequent deleterious effect on predictive accuracy. The predictive accuracy as measured by the c-index was 0.69 in internal validation. The nomogram was well calibrated, and there was good correlation between predicted and observed outcome across the spectrum of predictions (Fig 3B).
The ability of the nomogram to discriminate among patients for the outcome of SRT was compared with published models (based on PSADT, disease-free interval, and/or Gleason grade) developed to predict the probability of metastases2 and of cancer-specific mortality22,23 for patients with a rising PSA after RP (Table 2). The predictive accuracy of these models was marginally better than that expected by chance (c-index, 0.56 to 0.60) in our cohort, and substantially inferior to the nomogram. The c-index of PSA before SRT as a single parameter was 0.61.
Male 61 DX age 60
Father had PC
2002. Psa. .08. Enlarged Prostrate
2014. Psa. 3.8
2016. Psa. 19
3-08-17 RP Mayo Clinic Mn
Pathology Report: Gleason 9, Seminal vessels and one nerve cancerous and removed, negative on margins, 35 lymph nodes removed no cancer, tumor was pt3b. Prostrate 45 grams
4-20-17 Incarcerated Umbilical Hernia repair
6-13-17 1st psa check 0.13
7-19-17 psa 0.12 MRI clear