Pelvic lymph node treatment area is seldom wide enough

A Mayo Clinic study sought to determine exactly where the recurrences were after failure of prostatectomy. Parker et al.  studied recurrence in 41 patients who received a post-prostatectomy C-11 Choline PET/CT scan between 2008 and 2015, and at least one recurrence site was identified (median = 2). They were all candidates for whole pelvic salvage radiation, using at least 45 Gy of external beam radiation. They classified their recurrence sites as:

1. IF (in-field) if the recurrence site would receive at least 45 Gy
2. EOF (edge of field) if the recurrence site would receive less than 45 Gy (inadequate dose)
3. OOF (out of field) if the recurrence site would not receive any radiation

They identified 121 recurrence sites. A sizeable minority (43%) of the recurrence sites were within the whole pelvic radiation field; however, when they looked at how many of the patients were adequately treated for all their recurrence sites, a disturbing picture emerges:

• Only 12% had IF recurrences
• 24% had EOF recurrences (median dose - 10 Gy)
• 88% had OOF recurrences.
• 15% had both EOF and OOF recurrences.
• 10% had both IF and OOF recurrences.

It should be mentioned that the patients did not receive the PET scans until their PSA reached a median of 3.1 ng/ml (C-11 Choline PET isn't much good at PSAs lower than 2 ng/ml.) This occurred a median of 15 months after biochemical failure (PSA≥ 0.2 ng/ml). And biochemical failure occurred a median of 24 months after prostatectomy. We know that waiting this long is sub-optimal.

A similar study at Memorial Sloan Kettering looked at the site of failure after first-line radiation therapy to the prostate only (including seminal vesicles in some). They used CT scans (mostly) to detect sites of failure among 60 patients who had their first failure in the pelvic area. Spratt et al. found that, among those patients, only 42% would have the first detected lymph node metastasis treated by the standard pelvic lymph node radiation field. They found that by expanding the field to include the common iliac lymph nodes would treat 93% of recurrences.

A study at University Hospital Munich used F-18 or C-11 Choline PET scans to determine the site of lymph node involvement in 32 high-risk patients, and in 87 patients who were biochemically recurrent after prostatectomy. Location of lymph node involvement was similar for both groups, with 39% of pelvic LNs missed by the standard treatment field.

A similar study at the University of Kansas, using C-11 Acetate PET scans found that over half of all positive pelvic lymph nodes would have been missed by the standard radiation field. Notably, 78% of all positive lymph nodes were smaller than 1 cm, and therefore would have been missed if only a CT scan were used to identify them.

A similar study found that 39% of pelvic LNs would have been missed.

(Update 5/2019) De Bari et al. used a PSMA PET scan to identify sites of recurrence after prostatectomy failure. They found:

• 75% of patients had a nodal relapse outside of the traditional (RTOG) field
• To cover 95% of the nodal relapses, the radiation field size would have to be expanded to include the para-aortic lymph nodes up to T12-L1

The other common method of treating pelvic lymph nodes is via extended pelvic lymph node dissection (ePLND).  In one recent study, almost a quarter of positive LNs would have been missed even if ePLND had been used.

It is possible that as advanced PET scans gain wider use, detection of smaller pelvic LN metastases will be possible. Jelle Barentsz at Radboud University Hospital in Nijmegen, Holland claims he can detect LN metastases as small as 2 mm using USPIO MRI. Even so, we are far from being able to detect all micrometastases in the pelvic area. If the goal is curative therapy, it is necessary to treat what we can't see as well as what we can see.

Unfortunately, it is not always as simple as expanding the radiation treatment field or increasing the number of pelvic LNs dissected surgically. As the treated area is widened, the risk of side effects increase. Lymphoceles and lymphedema are potentially crippling side effects of surgical excision. Damage to the enteric tissue of the small bowel and vascular damage become risk factors with wider radiation treatment fields. For anatomical reasons, not everyone is a good candidate.

(Update 9/1/20) NRG Oncology expanded its recommendation for the treatment of pelvic lymph nodes (see this link).

Such risks have to be balanced against the evidence for the potential benefit of such treatment. The success of pelvic radiation in various settings was discussed here, and early results from the STAMPEDE clinical trial among N1 patients are encouraging.

We're still not very good at finding cancerous pelvic lymph nodes

(Updated)

Pelvic lymph node (PLN) detection is important because it is one of the first places prostate cancer travels to after leaving the prostate or prostate bed. Cancer cells in the interstitial fluid of the prostate drain out into sentinel LNs and then into many other LNs. The LNs act like filters, catching the errant cancer cells. Sometimes the white blood cells surround and destroy the cancer cells, but sometimes the cancer changes the white blood cells and lymph node tissue, creating a microenvironment that is more hospitable to cancer cells implanting themselves there and growing. It can take years for enough cancer cells to create such a hospitable habitat and grow to a size that can be detected with a scan. When it is detected there, it is called stage N1, and is called "locally advanced." In some cases, prostate cancer may still be cured if it is locally advanced. The standard ways of detecting cancerous pelvic lymph nodes (PLN) are via surgical removal or radiographic detection. Neither is very good.

CT Scan

The standard of care for detecting positive LNs is a pelvic CT scan with contrast. (Sometimes MRIs are used for this with no advantage other than billing for the hospital.) This is often done the same day as a bone scan for high risk patients. The CT detects the size of LNs, and suspicion of cancer is as follows:

• < 8 mm: not suspicious
• 8-11 mm: gray area
• ≥ 12 mm: suspicious

The problem with detection by size is that many small LNs may harbor cancer, and enlarged LNs may be enlarged due to infection or due to inflammatory processes in nearby cells. The problem with CT detection is that it's possible for a LN with cancer to be small, and the cytokines released by it to enlarge a nearby LN that does not bear any cancer. While a biopsy of an enlarged node may be difficult to perform, enlarged nodes that shrink with androgen deprivation is a sure sign that cancer was causing the enlargement.

Patients with fewer and smaller positive LNs have longer survival, so if the patient wants treatment for N1 prostate cancer, whether local or systemic therapy, it is best to use an alternative method of detection.

USPIO MRI

Ultra-small paramagnetic iron oxide (USPIO) particles accumulate in healthy LNs more than in cancerous LNs. The particles and their lack can be detected in LNs using MRI. Combidex (ferumoxtran) is a brand of USPIO that is now available for this purpose, but only at Radboud University in Nijmegen, The Netherlands. It can detect positive LNs with a diameter as small as 2 mm in some cases (see this link). It is better than a C-11 Choline PET scan, which has a size limit of 6 mm. (Update 2/7/23) Fortuin at al. reported on a new trial there comparing PSMA PET/CT to USPIO with MRI.  In the same 45 patients, all with high risk of cancerous LNs (before primary therapy or recurrent):

• PSMA PET/CT found 71 suspicious LNs in 25/45 (55%) patients -2.8 per patient
• USPIO w/ 3T MRI found 160 suspicious LNs in 33/45 (73%) patients - 4.8 per patient
• MRI only missed 19 of the PSMA-detected LNs, but found over twice as many, and upstaged ⅓ more patients

In 20 patients, they used a 7T MRI and found:

• 115 suspicious LNs in 17/20 (85%) patients - 6.8 per patient
• 91% were smaller than 5 mm (the PSMA PET/CT size limit)
• 63% were smaller than 3 mm (the 3T MRI size limit)

Most of the suspicious LNs were outside of the surgical pelvic LN dissection area.

The outstanding question is: what is the value of detecting every last cancerous LN?

PET/CT or PET/MRI

As we've seen, the currently best PET scan is the DCFPyL PET/CT, which has been approved in the US for high-risk and recurrent patients. Tumor to background ratios may be especially better than the Ga-68-PSMA PET/CT scans. DCFPyL detected 30% more positive LNs in the same patients. It has high specificity (95%) but low sensitivity (~ 40%). The Axumin (fluciclovine) PET/CT is less accurate (see this link). PET/MRIs, now available at a handful of US institutions will provide greater accuracy. Detection of small metastases (< 5 mm) is unproven even in the best of these scans.

Meredith et al. reported on 532 patients diagnosed with the Ga-68-PSMA  PET/CT after PSA recurrence following initial treatment with prostatectomy (425 patients) or RT (107 patients).

• Among those treated with primary prostatectomy, positive lymph nodes were detected in 68%.  
• Among those treated with primary RT, positive lymph nodes were detected in 40%.

(Update 11/14/17) Schmidt-Hegemann et al. reported on 129 patients diagnosed with the Ga-68-PSMA PET/CT:

• 20 patients were scanned before initial RT treatment
• 49 patients were scanned after PSA recurrence after prostatectomy
• 60 patients were scanned after PSA persistence after prostatectomy (PSA never became undetectable)

Positive pelvic lymph nodes were detected in:

• None in the pre-initial treatment group
• 16% in the PSA-recurrent group
• 33% in the PSA-persistent group
• Detection rates were about the same in patients with PSA< 0.05 ng/ml

Multiparametric MRI (mpMRI)

Multiparametric MRI is more specific than CT, but is no more sensitive at detecting positive LNs. In one study, only 57% were correctly staged with a DW-MRI.

Surgical pelvic lymph node dissection (PLND)

Surgical removal, or PLND, is usually performed at the same time as a prostatectomy. The surgeon looks for about 5-10 PLNs and removes them for pathological analysis. In the US, this isn't done routinely by most surgeons because it is usually negative (only about 5% of prostate cancer patients have PLN invasion when first diagnosed), there are often false negatives, and there are risks of lymphocele and lymphedema from it. There are two indicators that it may be advisable to perform a PLND:

1. Risk of PLN invasion is greater than 2% (or 2.6%) on a validated nomogram like this one based on PSA, Gleason score and stage, or,
2. Enlarged PLNs have been detected with CT or MRI

(Note: This recent nomogram based on European patients recommends ePLND when the risk of PLN invasion is at least 7%)

When cancer is found, sometimes wider removal of as many as 30 PLNs is performed, called extended PLND or ePLND. The hope is to find more infected LNs and remove them, all of them if one is lucky, but the ability to control cancer using ePLND is controversial and the subject of clinical trials. ePLND is difficult because LNs are nearly invisible, small, and difficult to find, obscured by more colorful tissue and sometimes hidden in the visceral fat. Unlike blood vessels, which branch out, lymph vessels are networked. ePLND yield may be increased by injecting a fluorescent liquid, called indocyanine green, into the prostate and letting it drain through the lymph vessels. Even so, this missed 24% of sentinel PLNs in one study. A magnetometer that finds iron oxide particles that accumulate in lymph nodes has been tried intraoperatively (see this link). Radiotracers that consist of a gamma emitter (Indium 111 or Technetium 99m) attached to a PSMA ligand have also been used intraoperatively for this purpose in some recurrent cases (see this link) . PET scans may be used to detect some of the larger nodes to be removed. ePLND is a more common practice in Europe than in the US.

Even the most thorough ePLND misses positive PLNs. In one recent study, almost a quarter of positive LNs would have been missed even if ePLND had been used. Metastases don't just stick in sentinel LNs (the first ones that drain from the prostate). This is unlike breast cancer, for example. Cancer may accumulate in a LN without being detectable in all the LNs upstream from it.

The definition of the PLN field  of whole pelvic radiation as defined by a consensus of radiation oncologists missed 44% of the positive LNs, in this study. A study of LN failures after whole pelvic radiation therapy found that more than half had a failure above the treated area.

Clearly, there is no imaging modality that will find all metastatic cells in the PLN area. Failure of either ePLND or whole pelvic radiation to adequately treat the pelvic LNs that are most likely to be positive is problematic. As the coverage/dissection area expands, so does the risk of side effects. Lymphedema and lymphocele may result from ePLND. Late-term damage to the upper bowel is a risk of increasing the radiation field (see this link).

Such risks must be balanced against the evidence for benefits of treatment. The success of pelvic radiation in various settings was discussed here, and early results from the STAMPEDE clinical trial among N1 patients are encouraging.