Prostate adenocarcinoma salvage EBRT post radical prostatectomy

• Prostate adenocarcinoma.

• Post radical prostatectomy.

• Detectable (≥0.1 ng/ml) and rising PSA.^r

• No evidence of distant metastatic disease (M0).

• ECOG 0-2.

Cautions

• Previous high dose radiation to the pelvis.

• Poor urinary and bowel function.

• Radiosensitising medications (e.g. methotrexate).

• Inflammatory bowel disease and/or history of adhesions/bowel obstruction.

• Bilateral hip replacement.

• Non-rheumatoid collagen vascular disorders.

• Cardiac implantable electronic devices (CIEDs).

• Selected patients with biochemical recurrence at low-risk of clinically relevant adverse outcomes (metastases, cancer-specific mortality) may be considered for observation.^r

• Early salvage (PSA ≤0.5 ng/ml) delivers more favourable biochemical progression-free survival and reduction in distant metastases.^rrr

• Link to nomogram  salvage radiation therapy.^r

• Consider delaying radiation therapy commencement to allow for improvement in urinary function.

• There is emerging evidence for the use of PSMA-PET for restaging at low PSA levels. PSMA-PET appears to have high specificity, but limited sensitivity. A negative PSMA-PET should not be used to justify omission of salvage radiation therapy.

• Consider a pelvic MRI scan if gross local recurrence suspected.

Androgen deprivation therapy (ADT)

• Consider use of ADT (especially if PSA >0.6 ng/ml).^r The optimal duration is yet to be defined, though some guidance with respect to patient, tumour and treatment factors is provided in a systematic review by Spratt et al.^rrr

Indications notes

• If gross disease is apparent, consider boosting gross disease up to 74 Gy.

• **Elective nodal irradiation is optional and can be considered in selected high-risk patients.^r

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Target volume guides

• FROGG Consensus Guidelines for post-prostatectomy prostate cancer.^r

• NRG oncology updated international consensus atlas on pelvic lymph node volumes for intact and post-operative prostate cancer.^r

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

Efficacy

The evidence supporting this trial comes from observational studies in addition to one small randomised trial.^rrr

The JCOG 0401 multi-centre Japanese phase 3 trial randomized 210 patients with biochemical failure post radical prostatectomy to either ADT alone (with bicalutamide 80 mg daily), or salvage radiation therapy (64.8 Gy/36 fractions to the prostate bed) with bicalutamide ADT commenced only upon radiation therapy treatment failure.^r The primary endpoint (freedom from treatment failure of bicalutamide) was defined as any of: PSA progression, clinical progression/recurrence, fourth suspension of bicalutamide due to toxicity, patient withdrawal from therapy, death, poor treatment compliance, or prolonged bicalutamide suspension (>12 weeks). At a median follow-up of 5.5 years, 5-year rates of freedom from bicalutamide treatment failure were higher in the radiation therapy plus ADT group (HR = 0.555, 95% CI:0.376-0.818). There was no significant difference in clinical relapse-free or overall survival. As expected, rectal and urinary toxicities were higher in the radiation therapy group, but toxicities of grade 3 or higher remained rare. Whilst the ADT chosen in this trial is not standard with respect to drug or dose, there remains an apparent significant benefit to salvage radiation therapy.

Figure 1. Results from the JCOG-0401 trial (A) five-year rates of freedom from bicalutamide treatment failure, and (B) clinical relapse free survival.

© Eur Urol 2020^r

Boorjian et al. analysed 2,657 men with biochemical failure post radical prostatectomy, of which 856 (32%) received salvage radiation therapy.^r  Median follow-up following salvage radiation therapy was 5.9 years and showed the salvage radiation significantly reduced the risk of local recurrence (HR = 0.12, 95% CI:0.06-0.26, p <0.0001), systematic progression (HR = 0.30, 95% CI:0.16-0.56, p = 0.0002) and delayed the need for ADT. Salvage radiation therapy did not increase overall survival in this group.

Trock et al. retrospectively analysed 635 men who experienced biochemical and/or local recurrence where patients either received salvage radiation therapy alone (n = 160), salvage radiation therapy plus ADT (n = 78) or no treatment (n = 397).^r After a median follow up of 9 years post radical prostatectomy and 6 years following recurrence, salvage radiation alone and salvage radiation plus ADT was associated with a significant increase in prostate cancer-specific survival relative to those who received no salvage treatment HR = 0.32, 95% CI:0.19-0.54, p <0.001, and HR = 0.34, 95% CI:0.17-0.69, p <0.003) respectively. The increase in survival was limited to men with a PSA doubling time of less than 6 months, and radiation therapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival.

The efficacy of salvage radiation therapy with respect to appropriate patient selection is difficult to interpret given differences in patient characteristics, treatment methods, duration of follow-up and definition of treatment failure in retrospective series. The series conducted by Tendulkar et al provides the following information:^r

• 5-year freedom from biochemical failure was 56% overall; 71% for those with a pre-salvage radiation therapy PSA level of 0.01-0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21-0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51-1.0 ng/ml (n = 533), 43% for those with a PSA of 1.01-2.0 ng/ml (n = 341), and 37% for those with a PSA >2.0 ng/ml (n = 323); p <0.001.
• Statistically significant variables (p <0.05) associated with freedom from biochemical failure include: pre-radiation therapy PSA level, Gleason score, extraprostatic extension, seminal vesicle invasion, surgical margins, ADT use and radiation therapy dose.
• Statistically significant variables (p <0.05) associated with increased risk of distant metastases include: higher pre-radiation therapy PSA, higher Gleason Score, seminal vesicle invasion, negative surgical margins and lack of ADT.
• There is no subgroup of patients with a rising PSA post-prostatectomy who will definitely not benefit from salvage radiation therapy.
• Published nomograms may aid discussions with patients. Link to riskcalc.org 

Adjuvant radiation therapy versus early salvage radiation therapy

The debate of adjuvant vs early salvage radiation therapy has been ongoing and until recently, there was limited evidence to make any conclusions. However, data from three key prospective randomised trials - RADICALS-RT, TROG RAVES and GETUG-17 - now provides guidance with more definitive conclusions likely in future reporting of final results.^rrr

ARTISTIC is a pre-planned series of meta-analyses of these three trials and has reported preliminary results for the first end-point (PSA driven event-free survival) after median follow-up of 75 months (GETUG-17, n = 424), 60 months (RADICALS-RT, n = 1396) and 78 months (RAVES, n = 333).^r In each of these trials, the vast majority of patients had positive surgical margins (63-100% of cohorts) and extra-capsular extension (69-100% of cohorts); whilst patients with seminal vesicle invasion (19-22% of cohorts) and Gleason score 8-10 (8-17% of cohorts) were under-represented. Radiation therapy dose and fractionation used was relatively standard, with GETUG-17 allowing 66 Gy in 33 fractions, RADICALS-RT allowing 66 Gy in 33 fractions (61% of cohort) or 52.5 Gy in 20 fractions, and RAVES allowing 64 Gy in 32 fractions. The trigger and timing for activation of early salvage radiation therapy varied slightly between trials, but broadly activation was PSA ≥0.1-0.2 ng/ml and rising, with radiation to be commenced as soon as possible after declaring failure (initially up to 4 months delay allowed in RAVES trial, which was later increased to 6 months due to accrual and toxicity concerns). A unified definition for biochemical failure included PSA ≥0.40ng/ml and rising, clinical progression, non-protocol use of ADT or death.

After 270 events (the pre-defined trigger for interim meta-analysis of ARTISTIC data was 240 events). From the total cohort of 2153 patients, 39.1% of the early salvage cohort had received triggered radiation therapy.^r The pooled hazard ratio for event free survival at 5 years was 0.95 (95% CI:0.75-1.21, p = 0.70) with results consistent between trials (heterogeneity p = 0.18, I2=42%). This indicates that adjuvant radiation therapy provides no biochemical advantage compared with surveillance and triggered early salvage radiation therapy.

Figure 2. Effect of radiotherapy timing on event-free survival

© Lancet 2020^r

There are a few general and trial specific caveats that should be noted when interpreting this data:

• Low numbers of patients with seminal vesical invasion or high Gleason grades makes extrapolation of data in these settings difficult
• There was some variation in the use of ADT and pelvic nodal irradiation between trials. ADT was mandated in GETUG-17 and just under 30% of patients in RADICALS-RT received ADT as part of an optional second randomisation (or as per off-protocol clinician preference). Both these studies also allowed nodal irradiation as per clinician preference, with just over 5% and just under 25% of patients receiving nodal treatment in the RADICALS-RT and GETUG-17 trials, respectively.
• Whilst RADICALS-RT and GETUG-17 were both superiority trials (where adjuvant radiation therapy was not proven to be superior), RAVES was designed as a non-inferiority trial. Using the 5-year bPFS data for adjuvant radiation from the EORTC 22911 trial, a non-inferiority margin was set to ensure 5-year event-free survival difference of less than 10% (i.e. HR = 1.48). Early salvage radiation therapy could not be proven non-inferior to adjuvant radiation therapy in this trial (HR = 1.12, 95% CI:0.65-1.90).
• Whilst the RAVES publication specifically notes that final toxicity data is yet to be published, the preliminary toxicity data is markedly higher than that of either RADICALS-RT or GETUG-17. Notably, whilst TROG has reported grade 3 or higher toxicities for early salvage radiation compared to adjuvant radiation as follows: urinary toxicity in 11% versus 16% of patients, respectively, and erectile toxicity in 75 % versus 80%, respectively. The GETUG-17 trial reports grade 3 or higher toxicities for early salvage radiation compared to adjuvant radiation as follows: urinary toxicity in 2% versus 6%, respectively, and erectile toxicity in 1% versus 4%, respectively. This is not accounted for by differing rates of proceeding to salvage radiation therapy, with 50% in RAVES and 54% in GETUG-17 having radiation. In the GETUG-17 trial, 53% of patients having early salvage radiation and 69%having adjuvant radiation had treatment delivery with 3D CRT. This was not reported in the RAVES trial and could possibly be a contributing factor to the differing rates of toxicities.

It is important to note, the reporting of biochemical progression-free survival, distant metastases-free survival and overall survival outcomes at a median follow-up of at least 10 years is needed prior to making definitive conclusions. In the interim, however, this data does suggest in an appropriately consented population early salvage radiation therapy may be an appropriate alternative to immediate adjuvant radiation therapy, with the benefit of either delaying or possibly completely avoiding radiation therapy and its' associated toxicities.

Dose of salvage radiation therapy

Data on the benefit of dose escalation in salvage radiation therapy remains primarily retrospective. One large prospective randomised trial (SAKK 09/10 trial) continues to mature with only toxicity data reported thus far, whilst one small trial has reported early results.^rrr

The phase 3 SAKK 09/10 trial recruited 350 patients from Switzerland, Germany and Belgium, between 2011 and 2014, randomising them to salvage radiation therapy doses of 64 Gy in 32 fractions versus 70 Gy in 35 fractions without ADT.^rr Thus far, only toxicity data have been reported, with biochemical relapse data still maturing. The 2015 report indicated that physician reported acute toxicity was similar between the arms, with grade 2 or greater acute gastrointestinal (16.6% versus 17.7%, p = 0.8) and genitourinary (13.6% versus 18.3%, p = 0.2) toxicities similar despite dose-escalation.^r However, quality of life analyses indicated more pronounced clinically relevant deterioration in urinary symptoms in the 70 Gy in 35 fractions arm (p <0.02). A recent 2018 update reported on urinary incontinence, found dose-escalation had no impact on recovery of post-operative incontinence at 3 months post-radiation (recovery in 44% versus 41%, p = 0.80), or de novo development of radiation-related incontinence (14% in both arms).^r Subsequent reports including biochemical relapse data may guide the most appropriate doses of radiation therapy to use.

Qi et al. published initial results of their phase 3 randomised trial comparing salvage radiation therapy to doses of 66 Gy in 33 fractions versus 72 Gy in 36 fractions, with the primary endpoint being biochemical progression-free survival.^r This study recruited 144 patients and following median follow-up of 48.5 months, found no difference in 4-year biochemical progression-free survival between the two unstratified groups (75.9% versus 82.6%, p = 0.299). Subgroup analysis indicated patients with Gleason scores of 8-10 had a significant improvement in 4-year biochemical progression-free survival with the 72 Gy in 36 fractions arm (55.7% versus 79.7%, p = 0.049). There were no significant differences in acute or late gastrointestinal or genitourinary toxicities. It should be noted this trial is limited by the small cohort size (powered to show 20% biochemical progression-free survival difference at 5 years) and the short median follow-up, though future reports may add further weight to this evidence.

Before these trials, the evidence base for selecting dose was based solely on retrospective series. A large systematic review and meta-analysis of 71 retrospective studies involving more than 10,000 patients was published in 2016.^r From the heterogenous data set available, the author found a sigmoidal dose-response curve with the TCD₅₀ being 65.8 Gy and a 2% increase in relapse-free survival seen for each 1 Gy increase in dose between 60 Gy and 70 Gy. This paper suggested doses of at least 66 Gy and even above 70 Gy may be required to maximise the chance of reaching the upper range of the dose-response curve. When excluding studies that utilised ADT, dose of radiation was still an independent predictor of relapse-free survival.

Figure 3. Sigmoidal dose response curve for PSA relapse-free survival versus salvage radiation therapy dose

© Radiother Oncol 2016^r

Each bubble represents an individual series and bubble size reflects the number of patients in each series. Data are well fit by the sigmoidal curve (Spearman’s rho = 0.444, p = 0.0001) and the fitted TCD₅₀ is 65.8 Gy. A 2% increase in relapse-free survival is achieved for each additional Gy.

This was supported by a multi-centre retrospective study involving 1108 patients from 10 centres in the USA.^r These patients had biochemical failure following radical prostatectomy (PSA >0.2 ng/ml and rising) and did not receive ADT whilst undergoing salvage radiation therapy. Whilst a significant difference in biochemical progression-free survival was shown when comparing those receiving ≥70 Gy versus <66 Gy (multivariate HR = 0.70, p = 0.02), no difference was seen when comparing those receiving ≥70 Gy versus 66-69.9 Gy. There was no association seen between radiation dose and risk of distant metastases. As well as radiation dose, Gleason score, pre-treatment PSA and seminal vesicle invasion were found to be independent predictors of biochemical progression-free survival on multivariate analysis.

Based on the data above, as well as the excellent tolerability of dose-escalation when utilising IMRT/VMAT techniques, dose-escalation to doses of at least 66 Gy appears to result in improved biochemical progression-free survival and should be offered to patients pursuing salvage radiation therapy.

Pelvic nodal radiation therapy

There is currently insufficient data to provide strong recommendations on the benefit of including pelvic nodal irradiation along with salvage prostate bed radiation therapy.

Concurrent androgen deprivation therapy (ADT)

A number of randomised trials have demonstrated the benefit of concurrent ADT in selected patients with salvage radiation therapy, however the optimal duration of therapy remains unclear.

The first major trial was the RTOG 9601 placebo-controlled randomised trial which enrolled 760 patients who had detectable PSA recurrence (>0.2 ng/ml) following prostatectomy.^r Patients were randomised to salvage radiation therapy (64.8 Gy in 36 fractions to prostate bed only) plus ADT (24 months of bicalutamide 150 mg daily) or salvage radiation therapy alone. At a median follow-up of 13 years, the ADT group had improved 12-year rates of overall survival (76.3% versus 71.3%, p = 0.04), prostate cancer-specific mortality (5.8% versus 13.4% p <0.001), distant metastases (14.5% versus 23%, p = 0.005) and biochemical progression-free survival (56% versus 32.1%, p <0.001). A subsequent sub-group analysis of this trial identified that while those with PSA >0.6 ng/ml, at time of salvage radiation, experienced an OS advantage (HR 0.61, p = 0.02), those with PSA ≤0.6 did not (HR = 1.16, p = 0.46).^r In fact, these patients had increased risk of other-cause mortality (HR = 1.94, p = 0.01) and grade 3 or higher late cardiac or neurologic toxicity (OR 3.4, p = 0.05).

Figure 4. Results from the RTOG 9601 trial

(A) Unstratified overall survival for radiation therapy versus radiation therapy plus ADT and (B) overall survival for patients with pre-treatment PSA >1.5ng/ml

© N Engl J Med 2017^r

Figure 5. Results from the RTOG 9601 trial secondary analysis

(C) overall survival for patients with pre-treatment PSA ≤0.60ng/ml and (D) Other-cause mortality for patients with pre-treatment PSA ≤0.60ng/ml

© JAMA Oncol 2020^r

The GETUG-AFU 16 trial randomised patients who had a rising PSA ≥0.2 ng/ml following radical prostatectomy, but without clinical evidence of disease, to receive salvage radiation therapy alone (n = 374), or radiation therapy plus short-term androgen suppression (6 months of goserelin, n = 369).^r Median PSA at baseline randomisation for both groups was 0.30 ng/ml (range 0.20-0.50). At a median follow-up of 9.3 years, patients who received radiation plus ADT were significantly more likely to be free of biochemical progression or clinical progression, 10-year PFS 64% versus 49% (HR = 0.54, 95% CI:0.43-0.63, p <0.0001).

Figure 6. Biochemical progression free survival from the GETUG-AFU-16 trial

© Lancet Oncol 2020^r

The RADICALS-RT trial will provide guidance regarding the optimal duration of ADT in the salvage setting (6 months versus 24 months).^r

Toxicity

A summary of the most clinically significant toxicities associated with this protocol are included in the table below: