PCa Commentary #113: OLIGOMETASTATIC PROSTATE CANCER — METASTASES DIRECTED THERAPY: Where Do We Stand?

A clinically meaningful goal of MDT is the postponement of androgen suppression therapy, while the more lofty goals would be to prolong survival or affect a cure in some patients. Current research is refining the criteria for selecting those men who will benefit most.

MDT targets isolated lesions that emerge following primary therapy.  In most studies to date this involves treating three or less but possibly five lesions with surgery or “spot welding” the metastases with focused radiation such as CyberKnife.

It has been two years since the Commentary discussed this issue in the March-April 2015 volume PCa Commentary Vol 92, 2015 and concluded “MDT is a promising approach for oligometastatic recurrence … but should not be considered the standard of care.”  Many studies have been reported since then.

What has been learned? 

We’ve learned that MDT is still not applicable for most instances of recurrent cancer, but there may be some selected men where MDT may significantly delay the need for androgen suppression. An important current debate is whether MTD should stand alone or be accompanied by androgen suppression.

The evolution of more sensitive imaging techniques is altering the detection of “oligometastatic cancer.” Most early studies relied on CT and technetium bone scan imaging both of which lack sensitivity. Currently the 11C-choline PET/CT (and similar tracers such as 11C-acetate) are serving as the basis for more sensitive detection, but even these scans will be superseded by application of the 68Gallium-PSMA PET/CT, for which currently there are no reported study outcomes.

The issue of imaging accuracy was discussed by Dr. Piet Ost, Ghent University, Belgium, a leading investigator of MDT.  In his interview in Dr. Charles Myers’ Prostate Forum, Vol. 17, No. 7 Dr. Ost made the following points:

  • In contrast to CT and bone scans, which most often require the PSA to rise above 10 ng/mL for adequate detection, now metastases are detected at PSA levels of 2 – 5 ng/mL by PET/CT scans utilizing tracers incorporating Carbon (C)-11 Fluorine and  (F)-18 isotopes. Most recently, 68Ga-PSMA PET/CT appears to have lowered the PSA level at which metastases can be detected to around 1 ng/mL.
  • The result: “We’re diagnosing a higher percentage of patients with a limited number of metastases.”  “If you try to divide these patients into those with Oligometastatic [i.e., <3]  and poly-metastatic disease, we see up to 60-70% of our patients in a recurrent setting diagnosed with a limited number of metastases at very low PSA levels.”

Does an intermediate disease state — oligometastatic cancer — exist and can it be treated with localized therapy to the benefit of the patient?

The concept that there is an “oligometastatic state” — one with restricted metastatic capacity having unique biologic characteristics — interposed between cure and widespread metastatic disease was hypothesized in an editorial by Hellman and Weichselbaum, J Clin Oncol, 1995. A thoughtful recent editorial by Tran and Antonarackis of Johns Hopkins “Altering the Natural History of Oligometastatic Prostate Cancer with Local Therapies: Reality Versus Illusion, J Oncol Practice, 2017, addresses this question:  “… is there a biologic difference between hormone-sensitive oligometastatic prostate cancer and polymetastatic prostate cancer,” i.e., are the 3 – 5 lesions addressed with MDT only the forerunners of yet to emerge more widespread cancer?

To date, however, a molecularly distinct biologic or genomic profile for this condition has not been established. The authors point out the need for “an understanding of the early metastatic process before the inevitable changes have developed in men with metastatic castration-resistant prostate cancer after the heavy selective forces of multiple systemic treatment regimens.”

Therefore, currently the definition of “oligometastatic” remains clinical.

Unanswered questions:

On the clinical level, however, the major questions are:

  • Can MDT delay ADT and for how long?
  • Which men are the best candidates for MDT, and are there prognostic markers that can guide optimal patient selection?
  • Can the unresolved issue of whether to perform MDT with or without concomitant ADT be clarified?
  • And lastly, can MDT extend prostate cancer-specific survival and delay the on onset of castration-resistance in comparison to the conventional practice of commencing ADT at the onset of the diagnosis of metastatic disease?

Of the many reported studies, two examples will suffice.

  1. “Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study,” Trigging et al., British Journal of Cancer, April 2017.

This study reports the outcome of MDT in 100 men who relapsed following primary therapy and were diagnosed with < 3 isolated lesions based on a 11C-choline PET/CT (96%) or a combination of CT and bone scan (4%). The median PSA at initial diagnosis was 9.8 and at recurrence, 2.4 ng/mL. The risk categories of the men based on D’Amico staging were:  low, 5%; intermediate, 21%; high, 43%; and very high, 31%. The number of lesions treated was one, 87%; two, 9%; and three, 4%. The mean time from primary therapy to metastases was 43.9 months.

The distribution of lesions were 15.8% in bone and 84.1% in lymph nodes, the majority of which were in the template used for extended lymph node dissection, except for 24.4% in the paraortic nodes.

What was the outcome The median post SBRT PSA was 0.81 ng/mL. PSA doubting time (PSA DT) was a predictor of ADT-free survival. Of those men with a doubling time of <6.4 months 42.9% and 21.4% were free of ADT at 1 and 2 years. In those men with a PSA DT of >6.4 months, freedom from ADT was seen in 71.5% and 51.2% at 1 and 2 years. Those men with Gleason score 7 or less fared better than those with a higher Gleason scores.

Comment: This study, with its very well-studied and numerically sufficient patient cohort can easily serve as a model for patient selection and treatment outcome, offering in selected men a useful delay of ADT.

2. The second example comes from Dr. Ost and colleagues: “Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis,” European Oncology,

“We focused on patients who were treatment naive, with the aim of determining if SBRT could delay diseases progression” — both distant and local, with a goal of estimating the delay in the start of ADT.”  SBRT was used to treat 119 study patients with three or fewer lesions. The risk categories were skewed to higher risk men. Imaging was performed with 11C-choline PET/CT in 92 men and with 18F-FDG PET/CT in 24. One lesion was targeted in 72.3%; two in 18.5%, and three lesions in 9.2%.  The primary site of metastases was in lymph nodes in 60% of patients (10% beyond the pelvis) and in bone 36% and viscera 3%. The median PSA at the time of metastases diagnosis was 4 ng/mL and the median interval after primary therapy was 4.7 years. The median PSA DT at the time of metastases was 3.9 months (range 2.9 – 6.9). Half of the cohort received a median duration of ADT of 2 months.

What was the outcome?  The 3- and 5-yr distant progression-free survival was 31% and 15% before starting ADT.  Local control was achieved in 93% and 92% at 3 and 5 years. The median time before starting ADT was 28 months. No grade >3 toxicity was observed.

Their conclusion: “SBRT for oligometastatic PCa recurrence is safe and associated with a prolonged progression-free interval. This is likely to result in a clinically meaningful period without ADT in patients with metastatic disease.”

A Randomized Trial Is Needed …  and a well designed one has completed accrual and data is maturing.

A reasonable criticism of the studies to date is that all were retrospective and subject to “lead time bias,” a misleading conclusion that an earlier diagnosis yields a better ultimate outcome compared to the same disease detected at its usual clinical presentation.

These issues have been addressed in an important protocol conducted by Dr. Ost with European collaboration. The title of the trial is “Non-systemic Treatment for Patients with Low-Volume Prostate Cancer,” NCT01558427. In this small trial 58 men were imaged with a 11C-choline PET/CT after relapse following local treatment with curative intent. Those with three or fewer isolated lesions were randomized between half who received MDT and were followed for PSA progression and those followed for progression without MDT. Follow-up PET/CT imaging is prescribed at a set rise of PSA or symptoms. In the event of local or distant disease progression or symptoms ADT is started. Patients have been stratified on the basis of a PSA DT of greater or less than 3 months and the initial location of the metastases.

The primary endpoint is to determine the interval in each cohort before ADT is required. Secondary endpoints are prostate cancer-specific survival and overall survival. As described by Dr. Ost, “One of the goals of this approach is to delay the start of palliative androgen deprivation therapy (ADT), with its negative impact on quality of life.” “The inclusion of an active surveillance arm will improve our insights into the natural progression of oligometastatic PCa.” (Ost et al., BMC Cancer, 2014)

A protocol of similar design (NCT02680587), but using a PSMA tracer, is sponsored by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and is currently recruiting participants (target: 54 men). The study’s completion date is estimated to be October 2018. Contact physician: Phuoc Tran, MD, PhD at tranp@jhmi.edu

BOTTOM LINE:

Progress has been made in the last two years in defining the best candidates for metastases directed therapy. A meaningful delay in the start of ADT of more than 2 years has been estimated for those men. A currently maturing randomized trial is an effort to validate these findings.

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