Showing posts with label mpMRI. Show all posts
Showing posts with label mpMRI. Show all posts

Wednesday, December 6, 2017

Use of mpMRI and PSMA PET/CT to aid in salvage radiation decision-making

Because the success or failure of salvage radiation (SRT) hinges upon whether micrometastases are already systemic at the time of treatment, evidence that the cancer is still local improves the odds that SRT will be successful.. One way of finding local tumors is to use multiparametric MRI (mpMRI). mpMRI can detect tumors down to about a limit of 4 mm, and may be able to find tumors even when their PSA output is low.

Sharma et al. at the Mayo Clinic retrospectively examined the records of 473 men who were treated with SRT and who had an mpMRI prior to treatment from 2003 to 2013. Among men with a pre-treatment PSA ≤ 0.5 ng/ml, 5-year biochemical failure was:

  • 39% among those with a negative mpMRI
  • 12% among those with a positive mpMRI

Adding mpMRI to the updated Stephenson nomogram (see this link) increased its predictive accuracy for PSA recurrence after SRT from 71% to 77%. Perhaps its accuracy would increase even further if the MRI was confirmed by a biopsy of the suspicious tissue to eliminate any false positives.

Like the detection of a positive margin in post-prostatectomy pathology, detection of a local tumor using mpMRI increases the probability that SRT will be successful. Although the radiation dose to the suspicious lesion can be boosted (see this link), it is unknown whether such a boost actually increases efficacy when the entire prostate bed is adequately treated. It is also unknown what effect it might have on toxicity. Moreover, it is hard to argue for a reduced dose elsewhere in the prostate bed because of the known limitation of mpMRI in detecting smaller tumors, and the multi-focal nature of prostate cancer spreading.

Emmett et al. at St. Vincent Hospital in Sydney performed a Ga-68-PSMA-11 PET/CT on 164 men with rising PSA (PSA range: 0.05-1.0 ng/ml) after prostatectomy who received SRT. After eliminating patients who also had systemic therapy, there were 140 evaluable patients. They had a pre-SRT PSA of 0.23 (interquartile range 0.14-0.35).  As expected, detection rates went up with increasing PSA;

  • <0.2 ng/ml: 50%
  • 0.20-0.29 ng/ml: 64%
  • 0.30-0.39 ng/ml: 67%
  • ≥0.40 ng/ml: 81% 
They only had 10.5 months of median follow-up, and defined a favorable PSA response to SRT as a decrease of at least 50% in PSA and a PSA ≤ 0.1 ng/ml (those receiving adjuvant ADT were eliminated from the follow-up PSA-response analysis). The results should be interpreted with caution because of the very short follow up and low sample sizes. A short-term PSA response only indicates local control, and may not endure if systemic micrometastases were present.

PET/CT was negative in 38% (62/164). 45% of those men (27/60) had SRT to the prostate bed, and 7/27 had SRT to the pelvic lymph nodes field too. In the "negative" detection group, 86% had a favorable PSA response to SRT. Unfortunately, more than half of the PET-negative men never received SRT. This should serve as a caution against over-reliance on PET/CT. PET/CT is not good at detecting micrometastases in the prostate bed. The prostate bed is also a difficult place to detect PSMA-avid cancer because of masking from urinary excretion. We also know little about the natural history of PSMA development in prostate cancer -- it  may very well be that earlier forms of the cancer that may not express PSMA may be most vulnerable to SRT. SRT should never be withheld from an area based solely on negative PSMA findings.

PET/CT was positive in the prostate bed only in 23% (38/164). All of them had SRT to the prostate bed, and 17/36 had SRT to the pelvic lymph node field too. In the "prostate-bed only" detection group, 81% had a favorable PSA response to SRT. Recent evidence indicates that pelvic lymph node SRT increases effectiveness (see this link). Radiation of the pelvic lymph nodes should be considered in spite of negative nodal PSMA findings.

PET/CT was positive in pelvic lymph nodes in 25% (41/164). 87% (26/30) of them had SRT to the prostate bed and to the targeted pelvic lymph nodes. In the "pelvic lymph node" detection group, 61.5% had a favorable PSA response to SRT. The entire pelvic lymph node field and not just isolated lymph nodes should receive SRT for the reasons stated above.

PET/CT was positive for distant metastases in 14% (23/164). Nevertheless, 60% (10/15) of them had SRT to the prostate bed (and, I suppose, to the entire pelvic lymph node field), and 6/10 had metastasis-directed SBRT too. In the "distant metastasis" detection group, only 30% had a favorable PSA response to SRT. Only 1 of the 6 who had metastasis-directed SBRT had a favorable PSA response. When there are known distant metastases, treatment of the prostate bed, pelvic lymph nodes, and of metastases remains a controversial treatment.

The PET/CT was a better predictor of SRT response than PSA, Gleason score, stage, or surgical margin status. The most valuable finding of this small, short-term analysis was that metastases can sometimes be detected at fairly low PSA (as low as 0.1 ng/ml), and it may be possible to rule out SRT in those cases. Conversely, when distant metastases cannot be detected, SRT success rates may be very good.

We will require longer follow-up, larger sample size, prospective studies to establish the utility of mpMRI and PSMA PET/CT in SRT decision making. The two imaging techniques are complementary - the MRI is not as PSA-dependent and is not masked by the urinary excretion of the radiotracer, while the PET scan is highly specific for cancer. Both are useless in detecting tumors with a dimension smaller than 4 mm, so it would be a mistake to think that what is detected is all there is.

Friday, August 26, 2016

Will Restriction Spectrum Imaging (RSI) MRI replace multiparametric MRI?

Researchers at the University of California San Diego have developed a new kind of MRI called restriction spectrum imaging (RSI-MRI) that seems to discriminate among Gleason grades 3, 4 and 5 with unmatched geographic precision.

Yamin et al. report on ten prostates that were scanned with RSI-MRI prior to prostatectomy. The prostates were then stained and tumors in them were examined at high resolution. (High resolution, in this study, was 75 micrometers per pixel). In all, 2,795 microscopic “tiles,” grouped to be the size of the MRI voxel, were examined by pathologists and assigned Gleason grades. (An MRI voxel is the minimum volume of matter that can be resolved by an MRI.) They found:
  • ·      RSI-MRI distinguished between cancer and benign tissue
  • ·      RSI-MRI distinguished between Gleason grade 3 and benign tissue
  • ·      RSI-MRI distinguished between Gleason grade 4 and benign tissue
  • ·      RSI-MRI distinguished between Gleason grade 3 and Gleason grade 4
  • ·      It distinguished grades with geographic precision down to the voxel level

In a retrospective evaluation of 33 pre-prostatectomy patients, RSI-MRI was found to more accurately predict prostate cancer and was more highly correlated with Gleason grade. In a similar retrospective evaluation of 28 pre-prostatectomy patients, both RSI-MRI and mpMRI were able to predict the primary Gleason grade across 64 regions of interest. However, RSI-MRI, but not mpMRI, could distinguish primary Gleason grade 3 from 4. In a group of 100 patients with Gleason scores ≥ 4+3, RSI-MRI significantly improved the accuracy compared to mpMRI alone. When combined with only a T2-weighted MRI, it compared favorably to mpMRI.

By comparison, a multiparametric MRI (mpMRI) does a very poor job at distinguishing Gleason grade 3 from benign tissue, and it is geographically much less precise. Even with mpMRI/ultrasound fusion repeat biopsies, known areas of cancer are missed about 30% of the time in men on active surveillance.

It may be a superior tool for staging as well. The same group reported on 27 pre-prostatectomy patients who were staged with MRI and with RSI-MRI. Extraprostatic extension was correctly identified in only 2 of 9 patients (22%) using MRI, but in 8 of 9 patients (89%) using RSI-MRI. It also correctly staged the remaining 18 patients.

To understand this technique, a brief review of multiparametric MRI is in order. Multiparametric MRI, as most commonly used for prostate cancer detection, employs 3 parameters (there are other parameters, like MR Spectroscopy, that are less commonly used):

1.     T2 weighting shows areas of different tissue types. Bone, fat, air, calcifications, fibrosis are dark; whereas edema, tumors, and inflammation are light. This shows the basic anatomic detail for the other parameters to be fused with.

2.     Dynamic Contrast Enhanced (DCE) MRI uses a gadolinium dye to show areas of blood flow. Tumors often have increased blood supply  (called angiogenesis) that does not penetrate well. Because DCE has a relatively low signal-to-noise ratio, features can be difficult to distinguish.

3.     Diffusion-Weighted (DWI) MRI shows water circulation in and around cells due to the water molecules’ Brownian (random) motion. Water flows easily around the glandular tissue of a healthy prostate, but as dense tumor cells proliferate, the fluid flow is hindered. These images suffer from spatial distortion, making precise localization for biopsies difficult. Obstacles created by inflammation and necrosis can create false positives.

RSI picks up where DWI leaves off. It detects water molecule motion within the cells. Unlike the hindered motion of water molecules around the outside of cells, cell walls restrict the motion of water molecules within their perimeter. As cancer cells proliferate in the tumor, there is increasing restriction detected. Unlike DWI, RSI does not suffer from spatial distortion and the signal-to-noise ratio is much higher; therefore, tumors stand out in sharper relief. It is unaffected by prostatitis and other tissue anomalies. There is also much less overlap in its ability to distinguish Gleason grades.

Compared to an mpMRI, which takes about an hour, it takes much less time to acquire the images. It is probably less subject to reader error as well. It is easy to see how this can become an important tool in monitoring progression in men on active surveillance, detecting cancer in men where suspicion remains after a first negative biopsy, and in detecting the tumor site for focal therapy and for focal salvage therapy after primary radiation or ablation therapy.

RSI was originally developed to detect and precisely localize brain tumors, and its use for prostate tumor detection is still in its early stages. We will have to have larger prospective trials to validate its use. There is a clinical trial in San Diego, which will obtain RSI-MRI images of high-risk patients before ADT, after ADT but before RT, and after RT.