PCa Commentary | Volume 145 – September 2020

Posted by Edward Weber | September 2020

PSA, PSA Dynamics, and Advances in Imaging: PSA and the PSADT (PSA doubling time) Guide the Management of Prostate Cancer.

“Following radical prostatectomy [and radiation therapy] for organ confined disease, approximately one-third of men will develop a biochemical relapse with a detectable PSA level.”  Quoted from “PSA Doubling Time and Absolute PSA Predict Metastases-free Survival in Men with Biochemically Recurrent Prostate Cancer after Radical Prostatectomy.” Markowiski et al, Clinical Genitourinary Cancer, 2019. The development of biochemical recurrence (BCR) is seen especially in men diagnosed with unfavorable risk intermediated-risk and high-risk cancer.

A ‘detectable PSA’ conventionally refers to a post-surgical value of > 0.2 ng/mL and after radiation therapy a value of 2.0 ng/mL above the lowest PSA obtained (the nadir). But these set points have been arbitrarily chosen. Researchers at the Mayo Clinic have argued for a value after surgery of >0.4 ng/ml maintaining that many men hover in the interval between 0.2 and 0.4 ng/mL for extended periods. 

A relevant study recently published (Hosseini et al., “Prostate Specific Antigen Nadir after Radical Cystoprostatectomy [the removal of bladder and prostate] in Patients with Benign Prostatic Tissue: A Benchmark to Define Biochemical Recurrence after Radical Prostatectomy” Urology Journal, 2019. In their study of 52 men the average residual PSA in men lacking a prostate was .037 +/- .031 (range from.002 to 0.1 ng/mL). They concluded that a cut off of 0.1 ng/mL “may be more precise in the era of early salvage treatment.”

The Role of PSMA and Axumin PET/CT scans at biochemical recurrence:

The concept of ‘localized disease’ has come under sequential redefinition as imaging techniques such as the Ga68- PSMA PET/CT-11 and subsequent refinements, i.e. 18F-DCFPyL PET/MRI, F-18 PSMA-1007 PET/CT and others find metastatic cancer at progressive lower PSA values, i.e. lower than 0.2 ng/mL.

After primary therapy a subsequent rise in the PSA alerts to the need for localization of the source of the PSA. Conventionally after primary treatment a value of PSA between 0.2 and 0.5 ng/mL occasions a CT and technetium bone scan.  ‘Salvage’ radiation is administered immediately or after a period of observation if those scans are negative for metastatic cancer. However, currently an Axumin scan is replacing these two less sensitive scans and frequently finds disease in locations that were negative on standard imaging. This leads to changes in the intended treatment plan in nearly half of the men.

The current most sensitive scan is the 68Ga-PSMA-11 PET/MRI. In the Journal of Nuclear Medicine, 2020,  Kranzburgher et al. reported a study of 66 men: “Detection Rate and Localization of Prostate Cancer Recurrence using 68Ga-PSMA-11 PET/MRI in Patients with Low PSA Values <=0.5 ng/mL.”  “The median PSA level was 0.23 ng/mL (range 0.03-0.5 ng/mL).” The Gleason scores of men in this study were Gleason 7, 54%; Gleason 8, 12%; and Gleason 9, 24%.

“An overall detection rate of 65% was observed in patients with PSA values between 0.2 and 0.5 ng/mL.” “Even at low PSA values of 0.5 ng/mL or lower, only 12.1% of patients had PSMA-positive recurrence limited to the prostatic bed, and extra pelvic disease was detected in 13.6% of the cohort.” In their conclusion the authors stressed that “PSMA /MRI detected PSMA positive lesions outside the standard radiation volumes in 40% of all patients,” findings that would likely change management plans. 

The earlier diagnosis of metastatic disease affords the opportunity of the earlier use of Provenge and Xofigo (Radium-223), both of which extend survival. Both of these agents are only approved for use for metastatic disease, in the case of Xofigo metastatic disease only in bone.

PSADT in the management of men progressing after salvage therapy.

If recurrence is found in the prostate bed after surgery or in the prostate itself after radiation, a second attempt to cure is usually attempted with radiation therapy. “Salvage radiotherapy [after surgery] without ADT in patients with BRPC and PSA <0.5 ng/ml resulted in a 48% disease-free survival at 6 years (vs 18% in the PSA >1.5 ng/mL subgroup), Stephenson, JCO 2007. 

In recurrences after salvage therapy if imaging shows limited oligometastatic spread (3-5 lesions), say, in one or two pelvic lymph nodes, in lymph nodes beyond the pelvis or in bone, targeted radiation with the CyberKnife is an option. However, in the face of continued PSA progression management now relies on the PSADT to guide the application of hormone or chemotherapy. The timing of this intervention is guided by considerations of the balance between the risk of early progression to metastatic disease vs. adverse effects of treatment.

Fortunately, men with low grade cancer, but also men with aggressive disease, can experience protracted survival, benefitting from the therapeutic advances in recent years. In order to evaluate and compare treatments in clinical trials at an earlier disease stage as compared with using overall survival as an end point, a surrogate for overall survival data was needed. The time from initial treatment to the development of metastases, i.e., metastasis-free survival (MFS), has been validated for this purpose.  “Following BCR, metastases-free survival predicts for overall survival,” (Markowiski) whether the MFS interval is short or long.

The Markowiski, Antonarakis, Patrick C. Walsh, Partin and Eisenberger (Johns Hopkins) article in review:

“The institution of systemic treatments is a subject of unresolved controversy.” The authors point out that early androgen deprivation therapy at biochemical recurrence can delay metastatic disease, however “it is unclear if this is associated with improvements in survival and quality of life.” Clearly, the decision to initiate androgen deprivation should be addressed in a serious conversation between patient and oncologist.

Risk factors that are associated with a shortened MFS are high Gleason score, time from primary treatment to BCR, high initial PSA, a short PSA doubling time, and initial tumor stage. With age the prostate gland grows and a PSA increase of 0.75 ng/mL/ year is acceptable.

From the Markowiski study of 31,000 men who had surgery at Johns Hopkins between 1983 and 2014, 656 men were selected who showed a BCR of >0.2 ng/mL and who also had a PSADT of <12 months. This cohort was followed, without androgen deprivation, until diagnosed with metastases based on CT, bone scan, MRI, or symptoms. (This is a protocol plan that could never be repeated today.)

Their findings:

“In a prior study (Antonarakis et al., BJU Int 2012) of a JHU cohort of patients with BRPC, we found PSADT < 9 months to be the strongest predictor of metastatic disease and prostate cancer-specific mortality. 

In the current study of 656 men, having relapsed after surgery with BCR >0.2 ng/mL, were followed without any adjuvant or hormonal therapy until metastases. ‘Prostate-specific antigen doubling time of < 7.5 months and Gleason score are independent predictors of metastases-free survival…” They reported that compared to Gleason score of 6, men with Gleason score 7 carried a 1.75 times greater risk and Gleason score 8 – 10 a 3.44 times greater risk of developing metastatic disease.

The author suggested that men with these characteristics might be considered for early androgen suppression.

BOTTOM LINE:

Increasingly sensitive imaging techniques are finding metastatic disease below the now conventional PSA levels chosen for biochemical recurrence. At biochemical progression after attempted curative therapy, the PSADT guides prostate cancer management.

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, & Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”