Metastases Directed Therapy (MDT) has become a realistic option for men who develop metastases after primary therapy. The theoretical foundation of MDT was succinctly stated by David Palma, M.D., PhD:
“The oligometastatic paradigm hypothesizes that patients with a limited number metastases may achieve long-term control, or even cure, if all sites of disease can be ablated. However, long-term randomized data to test paradigm are lacking.” JCO, Sept, 2020.
In the review, “What Is Oligometastatic Prostate Cancer? Fraser et al. (European Urology Focus 5, 2019) point out that “accumulating clinical evidence suggests that patients with oligometastatic disease have improved clinical responses from metastases-directed therapy. This suggests that tumors that gave rise to the oligometastatic state are distinct biologically and genetically from those that induce widely metastatic lesions.”
This Commentary will address the guidance from four clinical trials (the ORIOLE, STOMP, SABR-COMET and English observational trial) regarding patient selection and imaging choices to best select patients most likely to benefit from MDT.
The Four Trials; Their Findings:
A common finding among all four trials is that the treatment of several lesions with Stereotactic Body Radiation Therapy (hypofractionated radiation, eg., with CyberKnife), results in excellent local control (99% in the ORIOLE trial) with few > Grade 3 adverse effects.
- The English Study: (Chalkidou al., Lancet Oncl 2021) This trial studied the pattern of recurrence in 1422 men and women with a variety of cancers (28.6% prostate cancers). Imaging for recurrence employed a PET/CT, whole body MRI, CT or bone scan. Local control with SBRT at one year was 87%; at two years, 72%.
Take-away point: A single site of recurrence was found in 75.6% of patients; 19.5% had 2 sites and 4.8% had 3 or more. The number of metastatic sites was a significant prognostic factor. Having more than 1 site (in a study relating to lung cancer) doubled risk of a poorer survival.
- The SABR-COMET Trial:(Palma et al., JCO 2020) This was an international study of a variety of cancers at recurrence in men with 1 – 5 lesions comparing SBRT + standard care (ADT) v standard care. Imaging for recurrence employed PET/CT in 45%. Prostate cancer comprised 16%. “SBRT was associated with a 13-month increase in overall survival and a doubling of progression-free survival. The long-term local control for SBRT was 63%.
Take-away point: Again the number of metastases at recurrence was the most significant predictor of survival.
- ORIOLE Trial: (Phillips al., JAMA Oncology, Mar. 2020), is a study of 54 men treated with SBRT for 1-3 oligometastatic sites, none receiving ADT, followed for disease progression at 6 months. Outcome: 19% treated with SBRT progressed vs 61% undergoing observation.
Take-away point #1: Patient selection is optimal when treatment is based on a PSMA PET/CT. In this study men were treated with SBRT based on the baseline CT, MRI and bone scan, but also underwent an undisclosed pretreatment PSMA PET/CT. In the SBRT group, those men whose PSMA baseline scan showed no untreated lesions (i.e., no lesions other than those in the original staging) had superior outcomes. Only 5% developed distant metastases vs 38% in whom all the baseline metastases had not been treated.
Take-away point #2: Immunologic analysis of the SBRT cohort revealed a heightened activation of cytotoxic T-cells likely promoted by the releases neo-antigens from the treated lesions – a type of ‘vaccine’ effect, wherein activated cytotoxic T-cells attacked un-imaged micrometastases.
This trial does not address the important question whether better long-term outcome could be achieved by combining MDT with ADT, but rather researches the issue from the point of view as to whether MTD alone can achieve an ADT-free period of useful duration allowing postponement of ADT toxicity.
- STOMP Trial: Five-Year Results (Ost, ASCO GU, 2020) This 62-man trial, in which at baselineno men received ADT, addressed the issue whether SBRT to < 3 lesions would delay both progression and the institution of ADT. A choline PET/CT was done at baseline and sequentially. Progression was declared for development of > 3 new lesions. Local control was excellent and toxicity low.
Take-away point #1: At five years 34% in the SBRT cohort were ADT-free vs 8% in the control group, a 43.6% reduction.
Take-away point #2: At five years the SBRT group showed a 76% decrease in the risk of developing CRPC vs 53% in the control group.
Wrap-up conclusion based on the four cited studies:
Taken collectively, all four studies underscore the importance of evaluating prostate cancer recurrences with the currently most sensitive scans: a Ga68-PSMA or an Axumin PET/CT to identify the ‘oligometastatic’ state at its earliest presentation.
IMAGING for Oligometastatic Cancer
Where is the PSA ‘sweet spot’ in the balance between detecting cancer as opposed to obtaining an uninformative scan? The suggested range of PSA values in relation to detection rate can only be approximate since a positive scan depends on the size of the target lesion and its proliferation rate, with
~4 mm currently the lower limit of detection for the PSMA PET/CT for an avidly proliferative lesion.
Regarding PSMA sensitivity Perera et al., Eur Urol. 2016 summarized their review of 1309 patients and found that at biochemical recurrence positive scans were seen for the PSA categories of 0 – 0.2, 42%; 0.2 – 1, 58%; 1 – 2, 76% and for >2 ng/mL, 95%.
A similar quest was carried out by Armstrong et al., Urologic Oncology, March 2002, who reported the study of 115 men at biochemical recurrence. Their summary of rates of cancer detection:at PSA values <0.5, 54% positive; 0.5 – 2.0, 70.6% and at PSA >2 ng/mL, 91.5% positive.
Their caveat: “It is important to note, that it is still unknown whether or not earlier detection and treatment will change long-term oncologic outcomes.
BOTTOM LINE: Ongoing Challenge – is to identify a characterizing genomic biomarker signature to validate the existence of an oligometastatic ‘in-between’ stage of limited metastatic potential. Until found, management of men with only several metastatic lesions at biochemical recurrence will proceed on the basis of clinical factors.