Lymph Node Dissection [LND] & Salvage Radiotherapy [sRT].

[pjoshea13]

New Mayo study below [1]. For article, see [2].

When radical prostatectomy (RP) is a primary treatment option, it offers better 10 year survival than radiation. And if it fails, there is always salvage radiation therapy (sRT), which, however, is not offered with curative intent.

"Up to 50% of patients recur after ... sRT for ... PSA rise following ... RP."

"In total, 728 patients were identified; of these, 221 and 116 were diagnosed with BCR {biochemical recurrence} and CR {clinical recurrence}, respectively, during a median follow-up of 8.4" years.

"... the risk of BCR after sRT was inversely associated with the number of nodes resected at RP (hazards ratio [HR]: 0.98 ...). Increased extent of dissection was also independently associated with a decreased risk of CR after sRT (HR: 0.97 ...)."

"These data support the importance of an extensive LND at surgery and may be used in prognosis assessment when sRT is being considered."

The risk reductions aren't impressive, IMO.

I wonder what the crieria was for taking a greater number of lymph nodes? Hardly a random decision, surely?

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/295...

Eur Urol. 2018 Mar 12. pii: S0302-2838(18)30174-X. doi: 10.1016/j.eururo.2018.02.024. [Epub ahead of print]

More Extensive Lymph Node Dissection at Radical Prostatectomy is Associated with Improved Outcomes with Salvage Radiotherapy for Rising Prostate-specific Antigen After Surgery: A Long-term, Multi-institutional Analysis.

Fossati N1, Parker WP2, Karnes RJ3, Colicchia M3, Bossi A4, Seisen T4, Di Muzio N5, Cozzarini C5, Noris Chiorda B5, Fiorino C5, Gandaglia G1, Bartkowiak D6, Wiegel T6, Shariat S7, Goldner G8, Battaglia A9, Joniau S9, Haustermans K10, De Meerleer G10, Fonteyne V11, Ost P11, Van Poppel H9, Montorsi F1, Briganti A1, Boorjian SA12.

Author information

Abstract

Up to 50% of patients recur after salvage radiation therapy (sRT) for prostate-specific antigen (PSA) rise following radical prostatectomy (RP). Notably, the importance of lymph node dissection (LND) at the time of RP with regard to recurrence risk following sRT has not been previously determined. Therefore, we evaluated the association between nodal yield at RP and recurrence after sRT. We performed a multi-institutional review of men with a rising PSA after RP treated with sRT. Clinicopathologic variables were abstracted, and the associations between lymph node yield and biochemical (BCR) as well as clinical recurrence (CR) after sRT were assessed using multivariable Cox proportional hazards regression models. In total, 728 patients were identified; of these, 221 and 116 were diagnosed with BCR and CR, respectively, during a median follow-up of 8.4 (interquartile range: 4.2-11.2) yr. On multivariable analysis, the risk of BCR after sRT was inversely associated with the number of nodes resected at RP (hazards ratio [HR]: 0.98; 95% confidence interval [CI]: 0.96-0.99; p=0.049). Increased extent of dissection was also independently associated with a decreased risk of CR after sRT (HR: 0.97; 95%CI: 0.94-0.99; p=0.042). These data support the importance of an extensive LND at surgery and may be used in prognosis assessment when sRT is being considered.

PATIENT SUMMARY:

We found that patients who had increased number of lymph nodes resected at surgery had improved outcomes after the receipt of salvage radiation therapy. These findings support the use of the extended lymph node dissection at initial surgery and should serve to improve counseling among patients who require salvage radiation therapy.

Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Lymph node dissection; Prostate cancer; Salvage radiation; Survival

PMID: 29544737 DOI: 10.1016/j.eururo.2018.02.024

...

[2] renalandurologynews.com/pro...

More Extensive Lymph Node Dissection in PCa Improves Outcomes

Researchers found that a more extensive lymph node dissection during radical prostatectomy (RP) is associated with improved outcomes following salvage radiotherapy in men with rising PSA levels following RP, according to study findings published online ahead of print in European Urology.1

The study, senior authored by Stephen A. Boorjian, MD, Carl Rosen Professor of Urology at Mayo Clinic in Rochester, Minnesota, included 728 men with a rising PSA following RP treated with salvage radiotherapy. The median follow-up was 8.4 years (range: 4.2– 11.2 years). The investigators looked at clinical and pathologic variables and the associations between lymph node yield and biochemical recurrence (BCR) and clinical recurrence (CR).

On multivariable analysis, the researchers found that the risk of BCR after salvage radiotherapy was inversely associated with the number of nodes resected at RP. Increased extent of dissection was also independently associated with a decreased risk of CR. “The extent of dissection at the time of prostatectomy could, pending validation of these findings, be a prognostic variable for men being considered for salvage radiotherapy,” Dr Boorjian told Renal & Urology News.

The authors contend that there are several potentially clinically relevant implications from these new findings, including further support of the oncologic role for greater lymph node dissection with RP. Additionally, if these findings are confirmed by others, the extent of lymphadenectomy may be considered a prognostic variable in patients with BCR after surgery who are considering salvage radiotherapy. The researchers write that it could help guide counseling and improve clinical trial design.

Due to the retrospective, multi-institutional design of the study, there are significant limitations to the findings. The authors noted that the reasons for salvage therapies were not analyzed, and the timing of salvage therapies was not standardized. In addition, there may be systematic differences between men receiving whole pelvic radiation compared with fossa-only radiotherapy (RT). The team was unable to completely adjust for this factor. In this cohort, whole pelvic RT was utilized more frequently in pN1 patients (33% vs 3%), and the number of resected nodes was greater among patients treated with whole pelvic radiotherapy (median: 12 vs 9).

The association between nodal yield and BCR-free survival and CR-free survival persisted when the researchers only looked at pN0 patients. The researchers noted that molecular imaging may play an increasing role in guiding site-specific salvage treatment in the future.

Dr Boorjian offered some possible mechanisms by which more extended lymph node dissection (eLND) may be linked to improved patient outcomes in this patient population. For example, a more extended node dissection could improve the accuracy of pathologic staging. “This in turn may lead to an increased utilization of additional therapies which further improve patient outcomes,” he said. “At the same time, it remains possible that a more extended dissection eliminates a greater proportion of micrometastatic disease and thereby leads to improved cancer control.”

Aditya Bagrodia, MD, assistant professor of urology at the University of Texas (UT) Southwestern Medical Center in Dallas, said available guideline recommendations and meta-analyses are somewhat ambivalent regarding the role of eLND, and the article by Dr Boorjian and colleagues perhaps provides a compelling reason to consider eLND when performing RP. The American Urological Association (AUA) guidelines for localized PCa state that pelvic lymphadenectomy is “recommended for those with unfavorable intermediate-risk or high-risk disease.” European Association of Urology (EAU) guidelines state that performing pelvic lymph node dissection during RP fails to improve oncologic outcomes, including survival. However, it also includes a statement acknowledging that eLND dissection provides important information for staging and prognosis. “These widely utilized guidelines do not explicitly guide urologists regarding the performance and extent of lymphadenectomy,” Dr Bagrodia said. “Furthermore, there has been sparse high quality data to directly answer the question regarding benefit of lymphadenectomy and whether or not standard or extended lymphadenectomy is most beneficial.”

Understanding the harms associated with eNLD is important, he said. A recently published systematic review and meta-analysis in European Urology found that it is associated with increased operating time, blood loss, length of stay, and postoperative complications with no benefit in overall survival.2 However, there were benefits with respect to biochemical and clinical recurrence-free survival as observed in the new study.

Radiation oncologist Neil Desai, MD, assistant professor of radiation oncology at UT Southwestern, said that as with any retrospective dataset, potential confounders in baseline therapy—particularly the timing of adjuvant vs early salvage radiation and use of androgen-deprivation therapy—are hard to completely address even with statistical adjustments. “This limits the ability to uniformly recommend a procedure with added potential complication risk, particularly in patients with low risk for nodal involvement,” Dr Desai said.

RELATED ARTICLES

MRI Predicts Outcomes of Prostate Cancer Salvage Radiotherapy

Biopsy-to-RP Delay May Up Prostate Cancer Recurrence Risk

Extended PLND Not Associated With Short-Term Oncologic Benefits

James Mohler, MD, professor of oncology in the department of urology at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and chair of the National Comprehensive Cancer Network (NCCN) Guidelines Panel for Prostate Cancer, said that based on current data, the NCCN PCa treatment guidelines recommend that an eLND be performed whenever a pelvic lymph node dissection is warranted. He said the findings from the current study must be viewed with caution.

“The authors have used number of pelvic lymph nodes procured as a surrogate for extent of pelvic lymph node dissection, which is problematic, and advocated number of pelvic lymph nodes procured as a meaningful biomarker of response to salvage radiation,” Dr Mohler said. “The differences found in biochemical recurrence and clinical recurrence were statistically significant but so small as probably not to be clinically meaningful. Finally, such a retrospective review should not be advocated for clinical use until studied further.”

References

1. Fossati N, Parker WP, Karnes RJ, et al. More extensive lymph node dissection at radical prostatectomy is associated with improved outcomes with salvage radiotherapy for rising prostate-specific antigen after surgery: A long-term, multi-institutional analysis. Eur Urol. 2018; published online ahead of print. doi.org/10.1016/j.eururo.20....

2. Fossati N, Willemse PM, Van den Broeck T, et al. The benefits and harms of different extents of lymph node dissection during radical prostatectomy for prostate cancer: A systematic review. Eur Urol. 2017;72:84-109.

[Tall_Allen]

You misunderstood the study. It only showed that men who got a more extended PLND followed by SRT did better than those who got less extensive PLND followed by SRT. It did NOT compare whole pelvic SRT-only to ePLND-only. I'll write up a fuller analysis later. BTW, while Mayo participated, it was primarily a European study.

[pjoshea13 in reply to Tall_Allen]

I presented the abstract without reference to "whole pelvic SRT-only to ePLND-only", which isn't mentioned in the abstract. So what was the misunderstanding?

[Tall_Allen in reply to pjoshea13]

Your lead sentence is incorrect and has nothing to do with this study: "When radical prostatectomy (RP) is a primary treatment option, it offers better 10 year survival than radiation. And if it fails, there is always salvage radiation therapy (sRT), which, however, is not offered with curative intent."

[pjoshea13 in reply to Tall_Allen]

I disagree that it is incorrect, but it does have nothing to do with the study, of course.

And yet, the findings seem to make the case for RP stronger.

A] Here is a study involving high risk cases:

ncbi.nlm.nih.gov/pubmed/248...

"With an overall median follow-up of 76 months, 35 (9.3 %) men with high-risk PC died due to PC (23 in the RT group and 12 in the RP group). The 5-year estimates of cancer-specific survival rate for men treated with RP and RT were 96.5 % (95 % confidence interval [CI] 94.2-98.9) and 88.3 % (95 % CI 82.8-94.3), respectively."

B] From the Cleveland Clinic (EBRT v. RP):

ncbi.nlm.nih.gov/pubmed/252...

"Men receiving EBRT had higher 10-yr PCSM compared with those treated by RP across the range of nomogram-predicted risks of BCR: 5Y-PFP >75%, 3% versus 0.9%; 5Y-PFP 51-75%, 6.8% versus 5.9%; 5Y-PFP 26-50%, 12.2% versus 10.6%; and 5Y-PFP ≤25%, 26.6% versus 21.2%. After adjusting for nomogram-predicted 5Y-PFP, EBRT was associated with a significantly increased PCSM risk compared with RP (hazard ratio: 1.5; 95% confidence interval, 1.1-2.0; p=0.006)."

C] "We compared the effect of primary external beam radiation therapy vs radical prostatectomy for locally advanced prostate cancer."

ncbi.nlm.nih.gov/pubmed/285...

"A total of 1,429 men (48.69%) underwent radical prostatectomy and had a median followup of 11.47 years (IQR 6.17-17.17) years. A total of 1,506 men (51.31%) received external beam radiation therapy and had a median followup of 7.04 years (IQR 4.11-10.51, p <0.001). Patients treated with radical prostatectomy were at significantly higher risk for urinary and sexual toxicities (HR 1.93, 95% CI 1.66-2.24 and HR 5.50, 95% CI 3.59-8.42, respectively). However, they were at lower risk for gastrointestinal toxicities (HR 0.75, 95% CI 0.65-0.86) than those treated with external beam radiation therapy. Radical prostatectomy was associated with lower odds of androgen deprivation therapy 5 years after primary treatment (OR 0.53, 95% CI 0.41-0.69, p <0.001). External beam radiation therapy was associated with higher overall and prostate specific mortality (HR 1.41, 95% CI 1.09-1.82 and HR 2.35, 95% CI 1.85-2.98, respectively)."

D] "Long-term results of a randomized trial for the treatment of Stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities."

ncbi.nlm.nih.gov/pubmed/104...

"The progression-free and cause-specific survival rates at 5 years were 90.5% and 96.6% in the surgery group and 81.2% and 84.6% in the radiation group, respectively. The surgery group had better progression-free and cause-specific survival rates (P = 0.044 and 0.024, respectively)."

-Patrick

[Tall_Allen]

The studies you cited were based on patients treated too long ago to be relevant to decision making today. In the early 2000s a quantum change occurred in radiation dosimetry and technologies. Dose escalation turned out to be very much more curative and much lower toxicity than had ever been done previously.

Also, high risk men who get RT are about 10 years older and sicker than men getting RP. In spite of that, and after correcting for age and comorbidities, rates of metastatic incidence and prostate-specific survival in the modern era are about twice as good in men starting with brachy boost therapy than in men who started with surgery and may have had A/SRT;

pcnrv.blogspot.com/2018/03/...

[pjoshea13]

& yet:

"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."

-Patrick

[Tall_Allen in reply to pjoshea13]

I agree - it is very sad that utilization is down. brachy boost experts can be hard to find.

[Dayatatime]

TA and Patrick thanks for the insight on localized treatment options with advanced disease. It is confusing for a lot of guys because of the different opinions and studies. As Patrick stated in a different post it seems whatever way the wind is blowing.

Treatment options absolutely depend on the patient. I do believe some read these these posts and ask themselves why they do not get offered the treatment others have gotten. It is not a one size fits all treatment / disease. It also makes it very hard to do clinical trials because the average age advanced prostate cancer is diagnosed is 72. I believe it is 66 for cancer contained to the prostate. It just doesn't leave a very large percentage of younger guys to participate in anything proven.

The aggressive approach I was offered with the number of nodes I had extracted was no doubt offered because of my age being 46 at the time. I'm in good shape and the surgeon thought I could handle it and I did. Aside from ED I had zero issues. That was something I knew going into it and was willing to accept. HT treatment does the same thing. Had I been 30 years older I highly doubt I would've been offered surgery.

When a man is diagnosed at a younger age buying time with HT isn't enough until he dies of something else. Also even if the HT works for a time the effects of that are as bad as the disease itself. HT can kill you too and severely impacts quality of life.

The surgery and radiation debate all depends on the patient. At a young age I am an advocate of surgery. The scarring of radiation up front will leave your options very limited should cancer recur. Also radiation doesn't normally show any after effects early on and it's down the road side effects generally occur. There are studies that are now saying that salvage radiation may be overkill. Again, not proven but yet one more thing for a man to ponder.

With a Stage IV diagnosis there is no way a guy is going to get out of it unscathed. It is promising that there are doctors using the word curative with this prognosis. Nothing is proven but there are hundreds of cancer cases that have been cured with unproven treatments. If a guy isn't willing to take a chance he may never know what could've been.

Ron

[Tall_Allen in reply to Dayatatime]

Ron-

I very much agree that unless there are distant metastases, curative treatment should be the first option explored. Unfortunately there are myths about radiation therapy that you are repeating. Allow me to explain:

(1) "The scarring of radiation up front will leave your options very limited should cancer recur"

Actually, there are many good options for salvage treatment after primary radiation failure. See the table at the end of this article for a summary of them. While salvage surgery is an option, it's not a very good one - there are several better ones. BTW - salvage HIFU after RT was recently FDA approved, so insurance/Medicare should cover it.

pcnrv.blogspot.com/2017/09/...

(2) "Also radiation doesn't normally show any after effects early on and it's down the road side effects generally occur."

Urologists often say this, but the evidence is that it's just not true. Acute side effects are the bulk of all side effects and they occur within the first 3 months. Late term side effects of radiation are rare, but if they occur, they almost always show up within 2 years after RT. This was shown convincingly in the ProtecT randomized clinical trial:

pcnrv.blogspot.com/2016/09/...

(3) "There are studies that are now saying that salvage radiation may be overkill. Again, not proven but yet one more thing for a man to ponder."

I don't know what studies you are referring to, but the overwhelming data are that for men with adverse pathology and detectable (> 0.03) PSA, earlier salvage treatment saves lives:

pcnrv.blogspot.com/2018/01/...

- Allen

[Dayatatime in reply to Tall_Allen]

I received my information from a Professor of Radiology at MD Anderson (Dr. Deborah Kuban). She was kind enough to set up a phone conversation with me while I was seeking options when first diagnosed. She stated to me radiation can only happen once and putting all my eggs in one basket at my age should be considered. She told me I should consider surgery before radiation for that very reason and don't rule it out. She also explained the difficulty in treatment options after radiation is administered.

My surgeon from The Mayo Clinic (Dr. Jeffrey Karnes) explained how the scarring and difficulties because of it to me with surgery. Salvage surgery can be an option but the odds are more favorable for a successful outcome before RT. In fact I had scarring from chemo and previous hormone therapy that made my prostatectomy challenging.

I think you misunderstood my comment about salvage radiation. If a post surgery PSA is detected and adverse pathology is determined absolutely go for salvage radiation. I certainly would have and will if it deems necessary. If post surgery numbers are undetectable and pathology is favorable why cook your insides for nothing.

Everyone has opinions and there is nothing proven about treatment for advanced disease other than the elimination of testosterone suppresses it for only a time. What has worked for some hasn't worked for others and some have fared better with surgery and i'm sure some with radiation as well. Bottom line in my book is the one thing that is definite is death by cancer if diagnosed at an early age if some form of aggressive treatment isn't administered. Whether radiation or surgery a form of localized treatment seems to benefit a Stage IV diagnosis if mets are limited to nodes or oligometastatic.

Ron

[Tall_Allen in reply to Dayatatime]

I didn't mean to imply you were making it up. I know you were just repeating what you heard. So few doctors keep up, especially outside of their field. As you now know if you read those articles, the info you were told is out of date.

[Dayatatime]

Well let's just agree to disagree.

I was diagnosed in 2016 and had surgery in December of that year. The doctor that performed my surgery is Dr. Karnes whom is a specialist in bladder and prostate cancer. He is at the top of his game and authored and co authored several pubmed papers. To say he is not up to date on surgery, treatment and the disease itself would be grossly inaccurate.

Although I didn't work directly with Kuban what lead me to contact her was a pubmed paper she wrote about prostate cancer with lymph node involvement and the benefits of a localized treatment. She is a Professor of Radiation Oncology at one of the most prestigious cancer treatment hospitals in the world. To say she isnt current in her field would also be grossly inaccurate.

There are so many variables with this disease it's literally impossible to know what exact treatments will benefit what men and how they will respond. Both of the doctors I consulted with based their opinions on experience and a database of thousands of men who had treatment at both The Mayo and MD.

Ron