Declining use of RT in treating clinical stage T3 patients and those with adverse pathology after surgery


Patients clinically diagnosed with prostate cancer outside of the prostate capsule (stage cT3), are increasingly treated with radical prostatectomy (RP) rather than with primary radiation therapy (RT). In addition, patients who have adverse pathological features after first-line surgery (stage pT3 and/or positive margins) are increasingly not receiving either adjuvant or early RT.

Nezolosky et al. looked at the SEER database records of 11,604 patients clinically diagnosed with stage T3 prostate cancer from 1998 to 2012. They found:

  • RP use increased from 12.5 percent to 44.4 percent.
  • RT use decreased from 55.8 percent to 38.4 percent.
  • “No treatment” decreased from 31.7 percent to 17.2 percent.
  • For extracapsular extension (stage T3a), RP use was 49.8 percent vs. 37.1 percent for RT in 2012.
  • For seminal vesicle invasion (stage T3b), RP use was 41.6 percent vs. 42.1 percent for RT in 2012.
  • RT use exceeded RP by 59 percent if the biopsy Gleason score was 8-10.
  • RT use exceeded RP by 3 percent among those with higher PSA, and by 7 percent among older patients.

This trend is troubling because RP for cT3 is often not curative. The following biochemical recurrence-free survival rates have been reported and are very consistent:

  • Mitchell et al. (Mayo Clinic): 41 percent after 20 years for cT3 patients.
  • Freedland et al. (Johns Hopkins): 49 percent at 15 years for cT3a patients.
  • Carver et al. (Memorial Sloan-Kettering Cancer Center): 44 percent at 10 years for cT3 patients.
  • Hsu et al. (Leuven, Belgium): 51 percent at 10 years for cT3a patients.
  • Xylinas et al. (Paris, France): 45 percent at 5 years for cT3 patients.

The rates are similar among those diagnosed with stage T3 at pathology. Hruza et al. reported bRFS of 47 percent and 50 percent for those staged pT3a and pT3b respectively. Pagano et al. reported bRFS of 40 percent for those staged pT3b. Watkins et al. found that 40 percent of pT3 surgical patients had already biochemically relapsed after a median of 18 months.

There are other factors that affect recurrence prognosis after surgery. Age, a high pretreatment PSA level, a high Gleason score, positive surgical margins (including margin size and Gleason score at the margin), and the length of extraprostatic extension (EPE) are all risk factors (see Fossati et al., Djaladat et al., Ball et al., Jeong et al.). In the Watkins et al. study, patients with EPE and negative surgical margins biochemically relapsed at the rate of 0 percent, 28 percent, and 63 percent for Gleason scores of 6, 7, and 8 to 10, respectively. However, if the surgical margins were also positive, the relapse rates were significantly worse: 33 percent, 50 percent, and 71 percent for Gleason scores of 6, 7, and 8 to 10, respectively. Briganti et al. found that the 5-year bRFS was 55.2 percent among surgical patients categorized as high risk, which includes stage T3, Gleason score 8 to 10 or PSA > 20 ng/ml.

Can primary radiation alone do any better? I haven’t seen breakdowns for stage cT3 patients specifically, but we have long-term follow-up in many clinical trials where high-risk patients were treated with radiation and ADT. Here are some bRFS results we discussed recently:

  • HDR brachy monotherapy: 77 to 93 percent (3 to 8 years)
  • HDR brachy boost + EBRT: 66 to 96 percent (5 to 10 years)
  • LDR brachy monotherapy: 68 percent (5 years)
  • LDR brachy boost + EBRT: 83 percent (9 years)
  • EBRT monotherapy: 71 to 88 percent (5 years)

While primary radiation typically does about 50 to 100 percent better than primary surgery at controlling the cancer, urologists often argue that adjuvant or salvage RT will bring the numbers into line. There is an ongoing randomized clinical trial (NCT02102477) among men diagnosed with stage T3 comparing initial radiation treatment to prostatectomy plus salvage radiation. While we wait for those results, we have to rely on retrospective studies. In many of the studies cited above, about a quarter of the patients received salvage/adjuvant RT following surgery. In the Mayo study, 72 percent were recurrence-free after 20 years, which does bring the combination close to what radiation alone often delivers. However, that comes at a cost. Adjuvant and salvage RT usually has worse quality-of-life outcomes than the patient would have suffered had he had radiation to begin with.

This brings us to the second alarming trend: adjuvant and early salvage RT rates have been declining among men with adverse pathology after prostatectomy. We discussed this previously (see this link). So not only are T3 patients receiving a therapy upfront that is less likely to control their cancer, they also may not be receiving the adjuvant or salvage RT that might control it if used early enough.

It is especially troubling that there has been no corresponding shift to later salvage RT. Sineshaw et al. conjecture as to the reasons for the trend:

This pattern of declining use could be due to multiple factors, including patient preference, physician and referral bias, concern about toxicity, lack of a consistent survival benefit seen in the updated randomized trials, or a growing preference for salvage radiation at time of biochemical failure, rather than immediate adjuvant RT. With respect to the last point, our data did not show a rise in RT use after 6 mo and within the first 5 yr post-RP, suggesting that a shift to salvage RT does not likely entirely explain the declining use of immediate (within 6 mo) postoperative RT. [Emphasis added]

I’d like to believe that the decline in salvage radiation utilization is attributable to better selection of patients. Utilization was higher in those with positive surgical margins and those with Gleason scores 8 to 10. However, Dr. Sandler may very well be right in attributing the drop-off to urologists who don’t immediately refer patients with adverse pathology to radiation oncologists. In my experience, many patients making the primary therapy decision also never consult with a radiation oncologist. High-risk patients are especially needful of guidance from the first doctor they see — almost always a urologist — to seek second opinions. It would be unconscionable if they are not receiving that guidance.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

13 Responses

  1. I guess I can count myself “fortunate” — as a pT3b, Gleason 9 guy with EPE, positive margin and seminal vesicle invasion that: (a) I read a lot and (b) my local urologist (not my surgeon) agreed that once my PSA hit 0.2 post-op I needed ADT and SRT. But that was too late too since two iliac lymph nodes were determined to be suspicious and required radiation a year after SRT to the prostate bed was found to be inadequate.

    I’m not sure if any initial therapy would have resulted in a cure. Just hoping for durable (whatever that means) remission with minimal side effects.

  2. The conversation (or lack thereof) between surgeons and radiation oncologists and others about how best to manage localized prostate cancer is now well over 50 years old. It is way beyond time to resolve this problem. For some perspective, please see here.

  3. Sitemaster,

    Thanks for sharing. The overuse of surgery is based on a great deal of misinformation as to cure rates and flawed thinking that surgery should be done first because you can always do radiotherapy later, etc. Many of us have had surgery for appendix, tonsils, etc. and these surgeries are no-brainers with extremely high success rates and low rates of side effects/complications. … Particularly not so with prostate surgery in T3 situations.

    All prostate cancer patients need to do their homework. And those with clinical stage T3 really need to get a detailed diagnosis and thorough evaluation of alternative treatments. Exactly where are the tumors? What is the chance of recurrence at 5, 10, 15 years? Understand that salvage treatment after recurrence is complex and has low probability of success. We have all heard the oversimplified, absurd statement that surgery should be done first since it can always be followed by radiotherapy. As you have shown, the chances of surgery working are not good. Moreover, the probability of salvage treatment working is low, and the side effects/complications are poor. So, I would urge all T3 patients to explore alternatives in depth with a leading medical oncologist who specializes in prostate cancer.

    God Bless,

    John

  4. Dear John:

    Please appreciate that, from my perspective, the “overuse” of surgery is not the key issue. The key issue is “what actually works best?” as first-line treatment for men with intermediate- and high-risk prostate cancer. The truth is that we don’t have the relevant data and so we really don’t know. All that a knowledgeable medical oncologist can offer one today is yet another opinion, but that opinion is not based on any really sound data.

    Patients are better off from a data perspective if they actually have TxN+M0 disease. At least in that case we know — from Level 1 evidence — that the combination of radiation therapy + ADT offers a survival benefit compared to either ADT alone or radiation therapy alone!

  5. John:

    Nice thought but how is one to know that one is T3b before pathology? I was T1c after biopsy before going into RP and came out T3b. Is there a way to determine stage?

    Bob

  6. Bob:

    There is no absolutely certain way to determine pathological stage unless the relevant tissue is available for pathological examination.

    Multiparamtric MRI data may be helpful in determination of clinical staging and I am certainly aware of cases in which urologists have biopsied the seminal vesicles prior to treatment to determine whether the vesicles are positive, but that would be unusual in the majority of men who appear at initial diagnosis to be relatively low-risk (i.e., clinical stage T1c/T2a, Gleason 6 or 7, PSA < 10) but are subsequently found to have a higher pathological stage and grade.

    On the other hand, if you were known to be Gleason 9 based on your initial biopsy, there was always a significant possibility that you would be found to have positive seminal vesicles and positive lymph nodes, which could have been evaluated through the use of the Kattan nomograms.

  7. Sitemaster:

    So if one is Gleason 9 it sounds like RP should probably never be chosen; yet it is offered and chosen frequently. This sounds like questionable medical practice. I chose RP hoping to get lucky and with the view that I had SRT as a back up. And I was told that leaving a prostate behind with Gleason 9 prostate cancer had bad consequences. My open RP was indeed uneventful and no prostate cancer has been found in the prostate bed, but the subsequent SRT resulted in rectal bleeding which I’m going to have repaired. I also have complete and total ED … like ZERO function which existed post op and was probably exacerbated by SRT.

    In your opinion is there ever a justification for RP with high-risk prostate cancer at biopsy?

  8. Dear Bob:

    Any patient who is diagnosed with high-risk prostate cancer is at significant risk for subsequent progression regardless of their first-line treatment category. I don’t believe that your decision to have surgery was a bad one at all. I know of plenty of men with diagnoses similar to yours who show every sign of having been cured by surgical treatment. The problem is not the treatment. The problem is that we don’t have good enough diagnostic tests to tell men like you with high accuracy what your risk for progression is over time.

    With respect to the ED … I am sorry, but most men who have surgery and salvage radiation therapy are going to have very limited erectile function. Treatment for high-risk prostate cancer is not intended to save a patient’s sexual function. It is intended to try to save his life!

  9. Sitemaster:

    I did not intend to give the impression that I rued my treatments because of ED. I fully recognize and agree that survival is paramount; however, my surgeon did perform nerve sparing surgery so I hoped to have some function.

    You make the more important point that is the inability to tell patients their likely outcome from various treatment options given their risk factors. My surgeon did point out the nomogram I believe from Partin which showed (as I recall) 15-year prostate cancer-specific survival probability percentages for each type of pathology after RP. Given mine, I had about a 65 to 70% probability of surviving for 15 years.

    The problem with that nomogram is that it was not broken down by type of treatment post RP. I can only hope that, inasmuch as I have been very aggressive with subsequent treatments as I had BCR, I have increased my chances for long survival. Perhaps the data that Johns Hopkins is accumulating will lead to better prognostication years hence.

    Bob

  10. Clinical detection of T3 is rare, and is often difficult to detect. The vast majority of patients, even those who are otherwise high risk, are T1c or T2a. That’s why, when it is detected — either via biopsy, MRI or other advanced imaging — it must be taken very seriously. I believe that everyone diagnosed with cT3 should be referred to a radiation oncologist for consultation. The patient may choose surgery anyway, but the option of radiation should be given to him, along with a clear understanding of the risks and benefits attached to each option. In my experience with patients, their urologist often presents surgery plus salvage radiation as an equal alternative to primary radiation. It is not.

    Similarly, I believe that patients diagnosed at pathology with pT3 should be referred to a radiation oncologist for consultation. I stress consultation — not necessarily treatment. Many factors have to be considered to make a good decision about whether early salvage treatment is warranted, but the patient should be apprised of the risks and benefits, and monitored closely.

    I am very troubled by the trends cited in these two studies.

  11. Allen:

    After I was diagnosed as pT3b at pathology by Epstein, I got opinions from my local urologist, a local ROradiation oncologist and Dr. Han, the head radiation oncology at Johns Hopkins. All of them opined that I should have SRT to prostate bed and ADT of varying duration. The only dissenter was my Johns Hopkins surgeon who thought I should wait and attack recurrence when I had metastasis. I did not want mets. I can’t imagine any radiation oncologist saying “do nothing” given my prognosis.

  12. Thanks again Allen! Detection of stage cT4 men is significantly easier to confirm than stage cT3 men. There’s no doubt.

    We asked the following question of the SWOG GU committee members that were urologists again last month in Chicago: “How many of you performed surgery on men you knew had metastatic lesions?” and the response was almost all. In addition, M. D. Anderson is currently running a study on these men and the hypothesis is looking real. (Presented as well in the public session.) They appear live longer in prior studies. It would stand to reason it could be the same among cT3 men.

    I suspect that “debulking” the primary site can in fact help men live longer as this site is likely the source of a more advanced and aggressive tumor that can spread quickly. We’ll have to wait and see but the odds are in favor of this logic proving true. Of course the counter issue is when it does not help and the quality of life is degraded in elderly patients that would leave overall survival unaffected by such strategy.

  13. Many of us do see an RO post-surgery, and after careful consideration of the individual case decline adjuvant RT.

    The available studies are just not definitive for salvage RT at very low PSA levels, while the side effects of RT are real. There is an over-treatment issue here. The threshold between “early” sRT and late in the studies often cited is still a PSA less than 0.5. I for one would not wait that long, but there are no good studies showing a survival advantage where the cohort of patients received aRT while their PSA was zero. Furthermore, the RO may have a pecuniary interest, whereas the urologist does not. Who would you trust?

    This is a very difficult case by case decision. The patient must educate himself and be prepared to live (or die) by his decision; no one can make it for him.

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