Neoadjuvant Hormone Blockade
in Prostate Cancer

This article is an attempt to explain the rationale for considering neoadjuvant hormone blockade (NHB) in prostate cancer. Such a discussion is necessary because the scientific studies supporting this approach are still preliminary. They are so preliminary in fact that most doctors are not aware that these studies exist! Most of those who are aware are only aware in a superficial sense and have not thought through the implications of this new research and how it should apply to their daily practice. Although the scientific data in this area is only about two years old, patients who have prostate cancer now are forced to make the best treatment decision possible with the data currently available. We as prostate cancer specialists face confused and distraught patients who have talked to a variety of experts whose recommendations are as far apart as the moon and the stars. Our method is to offer an open and complete presentation of the treatment options available as of the present time, allowing our patients to draw their own conclusions. This short article will hopefully ease that process at least as it concerns decisions about neoadjuvant hormone blockade. The first half of this article presents a philosophical foundation of NHB. The second half presents the recent studies of NHB along with some comment. If you are fairly comfortable with the idea of NHB you may wish to skip directly to second half that is labeled "Recent Scientific Studies."

copyright Mark Scholz M.D. & Stephen Strum M.D.

Statistics

An intelligent discussion about the interpretation of medical studies cannot escape some reliance on statistics or at least simple percentages. Physicians who are seeing a new patient for the first time are usually asked to answer one very important question, "How likely am I to be cured?" Answering such questions can, in certain instances, be straightforward. But only in the circumstances where the outlook is either very good or very bad. The vast majority of men with prostate cancer are not such extreme cases. Predictions about the future for most of men have to be given in statistical terms. Likely or unlikely, or perhaps, probable or highly improbable, might be the typical terminology. Some doctors may even give percentages of likelihood in the fashion of: " 50:50 or 70:30." Other physicians might use ratios: "one out of three," or, "nine out of ten." The quality and reliability of these predictions are dependent on the quality of the underlying scientific studies. It is also dependent on the doctor's skill and ability to interpret and apply these studies to specific individuals.

Unfortunately the statistical approach to predicting the future for individuals leaves something to be desired. Statistics are very accurate at predicting averages for groups of people. Individuals, on the other hand may have a 10% chance of dying, but they cannot be 10% dead. We see this same dilemma illustrated in any phenomena that is all or none. When the weatherman predicts rain he may, for example, say there is only a 10% chance it will occur. Based on this hopeful report you proceed to make plans for a picnic. When the rains come down your only solace will be that nine times out of ten it should not have rained. You just happened to have bad luck this time around.

Study Endpoints

Scientific studies can usually only answer a single question. Most of the studies to be presented here are looking at the question, "does this form of treatment make you live longer." Unfortunately, from the study point of view, prostate cancer patients frequently live 10 or more years after diagnosis. Administering a treatment and waiting a whole ten years to see who lives the longest is usually impractical. Surrogate study end points that can act as early indicators of who will live longer or shorter are helpful in giving us quicker scientific answers (see below).

The Importance of Margins

One such surrogate endpoint in prostate cancer is a surgical finding called "positive margins." The finding of positive margins is a powerful predictor for the future recurrence of disease. What positive margins really means is that the cancer grows and extends outside the prostate and the surgeon has to cut through cancer to remove the prostate. This means that some cancer is likely left behind in the patient's body. Positive margins are such a negative indicator and associated with such high rates of metastatic recurrences that it raises the question if surgery should have been done. Since positive or negative margins are such powerful predictors of survival it enables researchers to do studies of NHB compared to no NHB using the surrogate marker of positive vs negative margins to get an indication about which of these differently treated patient groups will live longer.

Metastasis

Understanding the concept of metastasis is essential to making correct decisions about what kind of treatment is appropriate for your specific situation. It is important to realize that not only is it possible for the cancer to enlarge and grow out through the capsule of the prostate (increasing the risk of positive margins at surgery), but that the cancer cells can also separate from the tumor, enter the blood stream, and end up in other areas of the body- usually the bones. The concept of metastasis is a little challenging because often it is impossible to know with absolute certainty whether or not microscopic nests of metastatic cells exist. This is because there is no technology presently available that can scan your whole body and unfailingly detect the presence of a few prostate cells outside the gland. Bone scans are positive only when the metastasis provokes an osteoblastic reaction resulting in new bone formation. The bone scan isotope, 99mTechnitium-phosphonate, is laid down in the hydroxyapatite crystals near the metastasis. Our lack of ability in this area is a severe disability when it comes time to make treatment recommendations. Absolute information of course would be useful because we could then select the appropriate candidates for surgery, i.e. those with no metastatic disease. We would also know the individuals that surgery alone could not help.

Partin Tables

Absolute knowledge about metastasis would be very useful but is not available. There are however specific characteristics of the cancer itself as it manifests in each individual that gives information about how that cancer will likely act in the future. Prognostic indicators that are available before surgery are of course what are needed to help decide if surgery, or any local therapy for that matter, is indeed the right decision. Reliable predictors that can select out the men who are highly likely to have microscopic metastasis could enable many men to be spared unnecessary surgery! Fortunately three prognostic factors when combined together can be used to create statistical tables which predict the spread of cancer outside the prostate before surgery. They are called the Partin tables. The prognostic indicators used in these tables are the: 1]Clinical Stage of disease based on the digital rectal exam, 2) Gleason score based on the microscopic appearance of tumor, and 3) the PSA level. Men who have higher Gleason score, clinical stage, and higher PSA have a higher likelihood for spread outside the prostate. To derive the exact chance that any one patient has of having cancer outside the prostate his own factors are plugged into the tables and a percentage is given. There are several tables. One can predict for disease confined to the prostate. The other tables indicate the likelihood of capsular penetration, seminal vesicle and lymph node involvement. In practice this information proves very useful indeed. We consider the Partin tables to be a cornerstone in the rational management of patients newly diagnosed with prostate cancer.

Adjuvant Treatment

Why all this background? After all isn't radical prostatectomy the present state of the art, the gold standard. Urologists concede that 40% of men in this country who undergo radical prostatectomy are found to have positive margins. But are we forgetting the 60% who don't have positive margins? This latter group does very well with a relatively low incidence of relapse. Shouldn't we focus on the good instead of the bad.

Actually such arguments are very persuasive. In the past era where no one was even aware of alternatives, surgery alone made a lot of sense. At least some people got cured! More recently the medical oncologist has entered the arena of prostate cancer treatment. In the past this has been almost exclusively the domain of the urologist. Medical oncologists are cancer specialists whose training focuses more on the use of medications such as hormones and chemotherapy than on surgery. Oncologists are expected to be proficient in the treatment of over fifty different types of cancer whereas urologists in three or four. Oncologists bring a whole different perspective to the management of cancer. Yes , cancers from the breast or colon are different from prostate cancer. But there are also many similarities. Until good studies have been performed in prostate cancer it seems very foolish to ignore the principles learned fighting breast and colon cancer.

One extremely important principle that has been learned in these other diseases is the concept of adjuvant treatment. Adjuvant means medicines, chemotherapy or anti-hormones, added soon after surgery to improve cancer control rates. Breast cancer is a good example because, like prostate cancer, it is also a hormone dependent disease. Thirty years ago breast cancer was treated almost exclusively by general surgeons. The standard treatment was radical mastectomy. About twenty years ago an oncologist from Italy named Bonnadona, using statistics similar to the Partin tables, got the bright idea that chemotherapy, which has limited effectiveness in advanced metastatic breast cancer, might be strong enough to cure micrometastatic disease. He tested this idea and ultimately proved his case. Early treatment with chemotherapy and subsequently hormone therapy can cure micrometastaic breast cancer! His studies have been confirmed by numerous publications. Now chemotherapy and/or hormone therapy have become the standard approach to breast cancer in conjunction with surgery and sometimes radiation. We believe that this information should be of particular interest to prostate cancer patients. Prostate cancer is very similar to breast cancer in being a hormone-sensitive disease. However, the anti-hormone medications presently available to treat prostate cancer are much more potent and effective than the available anti-hormone treatments presently being used adjuvantly to cure micrometastatic breast cancer. It would seem therefore that our chances for a successful outcome treating prostate cancer adjuvantly should be high.

Neoadjuvant Treatment

The next important question is, "What is the justification for using adjuvant anti-hormones before surgery in prostate cancer when the successful anti-hormone studies in breast cancer have mostly used anti-hormones after surgery?" The simple answer is that while the disease may not be so different the anatomy is. In the case of breast surgery the general surgeon removes as much breast as is necessary to get all the tumor out. Breast cancer only rarely is so big that adjuvant treatment before surgery is required. The same is not true of prostate cancer because there is practically no space between the prostate and the adjacent organs. The urologist has practically no extra space around the prostate which is only the size of a walnut anyway. To get all the cancer out surgically, when the cancer extends outside the gland, is impossible unless he removes the bladder or rectum or both.

This leads us to one of the two powerful arguments for giving adjuvant hormone blocking before surgery. The idea is simply that effective hormone blocking therapy, which has the proven ability to kill prostate cancer cells, might be able to destroy enough cancer cells to alter surgical margins from positive to negative. Then local treatment such as surgical removal of the prostate gland would truly accomplish the goal of removal of all the cancer.

The second powerful argument for using adjuvant hormone blockade is related to the fact that leaving some cancer behind in the prostate bed (positive margins) is not the residual cancer of greatest concern. The residual cancer cells of the greatest potential concern are the undetectable micrometastatic cells in the bone that are so much more likely to be present whenever a man is demonstrated to have positive surgical margins. Why do I say tumor cells in the prostatic bed are less important? Because we know that men who ultimately die of prostate cancer do not die of progressive prostate cancer in the prostate bed: Men that die of prostate cancer die of metastatic disease in their bones, liver and/or lungs. The disease present in the prostatic bed is really of greatest concern because it is known to be a sign for metastatic disease. Above all we can not forget that positive margins are known to be a powerful predictor for future metastatic relapse.

Recent Scientific Studies: The main reason for this article

To this point we have only presented you with extrapolations and reasonable projections based on established principles developed in other types of cancer. We have been presenting these ideas to patients now for over five years. Many patients have decided to use NHB in their treatment approach.

In the last two years, from 1993 to 1995, and increasing number of medical publications about NHB have been published. It is no surprise to us that these new studies convincingly support the contention that neoadjuvant hormone blockade in prostate cancer is effective.

We began treating patients with NHB more than five years ago based on the thoughts and ideas presented above. The results of these initial patients from our practice were compiled and presented in an abstract in the Proceedings of the American Society of Clinical Oncology in 1994. In that study 24 patients were treated with a minimum of 6 months of Neoadjuvant hormone blockade using Lupron and Flutamide. These patients were all rebiopsied or underwent radical prostatectomy after completing six months of hormone blockade. Rebiopsy enabled us to obtain some solid information about the effectiveness of this new approach. The results showed that 18 of the 24 patients or 75% had no evidence of residual cancer by biopsy. Our interpretation of these preliminary results is not that six months of hormone blockade cures prostate cancer (though it may sometimes). Rather it does convincingly indicate that hormone blockade dramatically reduces the size of the prostate cancer. In medical terms, the tumor burden is significantly reduced. This is not masking of tumor nor is the tumor dormant. It is tumor cell kill mediated by androgen deprivation. Not all, but most of the prostate cancer cell population is dependent on male hormones or androgens for cell viability and replication.

Several important abstracts (preliminary studies) were presented at the annual meetings of the American Urologic Association and the American Society of Clinical Oncology in 1995. The main theme of these studies is NHB followed by radical prostatectomy compared to radical prostatectomy without NHB.

ABSTRACT # 650

Dr. Mark Soloway from Miami, Florida presented findings from a study of 303 men. These men were randomized into two groups. One group went straight to radical prostatectomy. The other group was treated with three months of Lupron and Flutamide. The groups were matched so that there was a similar dispersion of PSA levels in both groups. The incidence of positive margins in the first group was 47%. The incidence of positive margins in the NHB group was 17%. Dr. Soloway commented on these findings and noted that," the men that did not receive NHB were 6.2 times more likely to have positive surgical margins."

ABSTRACT # 337

Dr. William Fair from New York presented findings from a study done involving 184 men with a mean PSA of 16. These men were also divided into two groups, one of which received three months of Lupron and Flutamide. The NHB group had an 11% incidence of positive margins. The incidence in the surgery only group was 36%. Three patients in the NHB group had no cancer at all in the removed prostate. This study also presented preliminary results about the cancer relapse rates out to two years after surgery. Importantly they found that the cancer relapse rates in the men who had margin negative disease as a result of NHB was just as low as the relapse rates in men who had margin negative disease without NHB. We believe this is an important finding because many urologists are discounting negative margins achieved by NHB saying that margins obtained in this fashion will not translate into lower relapse rates.

ABSTRACT # 651

Dr. Knud Pedersen from Sweden presented his findings in 126 patients treated with 3 months of Triptorelin(similar to Lupron) combined with only three weeks of Androcur (Cyproterone acetate or CPA). CPA is a steroidal anti-androgen which is inferior to Flutamide. They also randomized patients between NHB followed by radical prostatectomy and direct radical prostatectomy. The incidence of positive margins in the NHB-treated group was 24%. The no NHB group had an 46% incidence of positive margins.

Abstract # 103

Dr. Larry Goldberg from Toronto, Canada presented his findings in 213 patients. These patients were randomized between no treatment prior to surgery and 3 months of Androcur as a single agent prior to surgery. No Lupron or similar type drug was used at all. Positive margins were 64% in the no Androcur group. They were 34% in the Androcur arm. Three patients in the Androcur group had no cancer at all in the removed prostate.

All these studies use no more than 3 months of hormone blockade. Some of them use less than optimal drugs as well. Despite these disadvantages all the results were indicative of favorable results from treatment with NHB. There were no studies presented that showed no effect or an adverse effect from NHB. The duration of hormone blockade is an important question. We know that it has taken years for the prostate cancer to develop. Maybe only 3 months of hormone deprivation is not enough. The following abstract addresses this issue.

ABSTRACT # 653

Dr. Martin Gleave presented findings on a relatively small group of 36 men who were treated with 8 months of NHB They observed (as we have also) that the PSA usually does not reach zero within three months. Eight months of treatment however resulted in 85% of the men having PSA levels that were undetectable. The positive margin rate in this group of 36 men was five percent! In our clinical experience the maximal benefit in reduction in prostate size appears to occur at 4-6 months rather than in the first 3 months.

TWO OTHER ARTICLES:

The abstracts presented above are not the only data available on this topic though they are the most recent. Two key studies examining the same question have been previously published in the Journal: "Clinical and Investigative Medicine." Fernand Labrie from Laval University, and the pioneer in the use of combination hormone blockade, was the lead author on the first randomized study of NHB involving 142 men treated with 3 months of Lupron and Flutamide. The NHB treated patients had a 13% incidence of positive margins while the untreated patients had a 38% incidence of positive margins.

Dr. Hugh Solomon from Crittenton hospital in Michigan presented the results of another similar study. He studied 200 patients treated with 3 months of Lupron and Flutamide with a reduction in margin positivity of 35% down to 11%. He also reported on a small subgroup of 20 patients with stage C disease. Some of these Stage C patients were treated with 6 months of NHB rather than 3 months. The group that had 6 months of treatment had rate of margin positivity that was one-half the rate of the group that had only 3 months of NHB.

COMMENT:

Clearly these studies provide strong support for the idea that neoadjuvant treatment in prostate cancer will be beneficial. As mentioned above, these favorable results are not any surprise to us given that the same successful principle has already been proven in three other common types of cancer: breast, colon, and lung cancer. The toxicity of hormone blockade is mild to moderate, reversible and should rarely be a deterrent. Most importantly, hormone blockade not only shrinks the primary tumor in the prostate, but it is also active against microscopic metastatic disease. We believe, based on the proven benefit of early adjuvant treatment in at least three other common types of cancer, that early hormone treatment of prostate cancer will ultimately prove to dramatically lower the incidence of recurrent metastatic disease.

 

Study Group        % Surgical margins  % Surgical margins
                       without NHB         with NHB 
                   (# of patients)     (# of patients)
                                        with 3 mos CHB


Labrie et al.1993      38.5% (65)         13% (77)
Fair et al.  1993      33% (72)           10% (69)
Solomon et al.1993     35.3% (119)        11.5% (156)
Fair et al. 1995       36% (92)           11% (92)
  update
Gleave et al.1995   Not Randomized        5% (36)--8 mos CHB 
Soloway et al.1995     47% (144)          17% (137)
 
Totals                 39.2% (420)        13.5% (462) 
                     Excluding Fair's    Excluding Gleave 
                         1st Group                    

Thus, in 4 randomized studies from different institutions, the percentage of pathologically positive surgical margins (PPSM) in patients undergoing RP without NHB has been essentially identical. The benefit of 3 months of NHB with a reduction to approximately 13.5% from 39% of PPSM in all 4 studies attests to the validity of these findings. The reduction to 5% in one non-randomized study raises the issue of what is the optimal treatment time with CHB in a neoadjuvant setting.

The long-term effects on survival with NHB are not available. The time in follow-up of patients receiving NHB has been too short for this determination. In Fair's study, the NHB subgroup with pathologically organ-confined disease (no surgical margin + , seminal vesicle + or node + patients) have shown the identical iochemical PSA relapse rate as those patients having RP only with pathologically organ-confined disease. Therefore 3 months of upfront CHB before RP appears to be having a biological effect on relapse. It appears to be not just "masking disease" as some opponents to CHB and NHB claim. The median follow-up time in the Fair et al study is 24 months. Further follow-up over the next 5 years will be critical in the assessment of the value of NHB on survival. For the time being it is reasonable to receive NHB.

                Mark Scholz M.D.   Culver City, California
                Stephen Strum M.D.  F.A.C.P.   September 1995

Prostate Cancer Research Institute (PCRI)

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