Monday, February 13, 2017

For very high-risk patients, EBRT + BT is superior to surgery or EBRT only (Redux)

In August, Kishan et al. showed a preliminary analysis of oncological outcomes among Gleason score 9 and 10 patients treated with brachy boost therapy (EBRT+BT), external beam radiation therapy alone (EBRT) or surgery (see this link). Because of the limited sample size, some of the differences were not large enough to be statistically significant. Kishan et al. have now expanded their analysis to include 1,001 patients treated between 2000 and 2013, who were treated at several of the top institutions in the US: UCLA, Fox Chase, Cleveland Clinic, Mt. Sinai, and Wheeling Hospital. So far, only an abstract of the study has been presented at the GU Conference. The patient characteristics were as follows: 
  • 324 were treated with radical prostatectomy (RP).
  • 347 were treated with EBRT only.
  • 330 were treated with EBRT + BT (BT was either low dose rate or high dose rate).
  • All patients were Gleason 9 or 10 on biopsy.
Treatment specs
  • Among the RP patients, 40% had adjuvant or salvage radiation therapy (68 Gy).
  • Among radiation patients, 90% had adjuvant ADT
  • Median dose of EBRT was 78 Gy.
    • adjuvant ADT continued for 18 months, median.
  • Median equivalent dose of EBRT+BT was 90 Gy
    • adjuvant ADT continued for 12 months.
Oncological outcomes

After a median follow-up of 4.8, 6.4 and 5.1 years for EBRT, EBRT+BT and RP, respectively, the oncological outcomes were as follows:
  • The 10-year rates of distant metastases were
    • 39.9% for RP 
    • 34.2% for EBRT
    • 19.7% for EBRT + BT
    • Differences between EBRT + BT and the two others were statistically significant.
  • The 10-year rates of prostate cancer-specific mortality (PCSM) were
    • 20.3% for RP
    • 25.2% for EBRT
    • 14.1% for EBRT + BT
    • Differences between EBRT + BT and the two others were statistically significant.
The authors conclude:
Extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT arm. 
Prostate cancer-specific mortality rates were cut in half by combining EBRT with a BT boost. While this does not prove causality (only a randomized clinical trial can do that) it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high risk patients may have to forgo brachy boost therapy in favor of high dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy with ADT will probably be the best choice.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

Friday, February 3, 2017

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.