Immediate versus Delayed Therapy for Prostate Cancer: Earlier is Better

E. David Crawford, M.D.
Professor of Surgery and Radiation Oncology
University of Colorado Health Sciences Center
Denver, Colorado

Prostate Cancer is the most common cancer diagnosed in American males. Just a decade ago, the majority of cases were detected when advanced and incurable. Thanks to heighten public awareness and early detection efforts, most cases that are discovered this year will be localized and potentially curable. Nevertheless, a significant number of patients still present with a stage of the disease where there is a risk of recurrence after local treatments such as surgery or various forms of radiation therapy. Researchers in the area of breast cancer treatment did studies years ago that have demonstrated the benefits of adjuvant therapies in certain women with breast cancer. The word adjuvant means that something is added to the primary therapy (surgery or radiation to brat tissue) such as hormonal therapy and or chemotherapy. We know that prostate cancer is a hormonally sensitive cancer. Withdrawal of the male hormone testosterone has been the mainstay of therapy for men with advanced disease for nearly 50 years. This article examines the current information regarding the use of such therapies earlier in the course of prostate cancer. It reviews what is known about hormone therapy and chemotherapy in various stages of prostate cancer and outlines a strategy for future research.

Introduction
The use of hormone therapy in most patients with advanced adenocarcinoma of the prostate produces a dramatic positive response followed by a disappointing progression. One reason for this is that in many cases, the treatment is with held until late in the disease known as advanced prostate cancer. Can the grim prognosis of advanced prostate cancer be altered through the use of novel agent and innovative? Or can outcomes be improved by delivering hormonal therapy earlier in the disease? Likely so, but the solutions are not imminent. Where is the field now? What do we know about current treatments?

Spectrum of Advanced Prostate Cancer
The 2 major challenges that patients with prostate cancer face are biochemical failure and hormone refractory disease. Widespread screening has resulted in a marked reduction in the diagnosis of advanced prostate cancer. More patients with “curable” lesions are being treated. In fact, nearly two thirds of newly diagnosed patients are treated either with radiation or surgery. Unfortunately, a significant percentage of these treatments will fail, as manifested by a rising PSA which signals that the treatment has failed. This stage (D1.5), in which PSA rises after failed local therapy and biochemical failure occurs, is the most common presentation of advanced prostate cancer.

Table 1 outlines this new spectrum of advanced prostate cancer that we described several years ago. As already discussed, just a decade ago, most men diagnosed with prostate cancer presented with disease in their bones. This is advanced, but advanced to patients include any point in the prostate cancer disease spectrum which threatens their life expectancy. And a rising PSA after failed local therapies is such a threat in many men with a long life expectancy.

Table 1. New Spectrum of Advanced Prostate Cancer

D1                   Pelvic lymph nodes

D1.5                Rising PSA after failed local therapy  

D2                   Metastatic disease in bone and/or other organs

D2.5                Rising PSA after nadir level

D3                   HRPC (hormone refractory prostate cancer)

Stage D1.5 (Biochemical Failure)
Stage D1.5 prostate cancer represents a unique opportunity in human oncology in that the patient has minimal tumor burden and that there is a marker, PSA, that can be used to ascertain progression and response. A diversity of opinions exists regarding treatment of these patients. Options include local radiation for prostatectomy failures, salvage prostatectomy for radiation failures, cryotherapy, observation and various types of hormone therapy. Most clinicians agree that once this state of rising PSA occurs, death from prostate cancer is inevitable if the patient is young and/or healthy (<50 years old or has a >10-15-year life expectancy). The patient exhibiting this type of PSA-only recurrence is usually offered one of the above-described treatments but many fail again with a rising PSA. This is the second challenge, a rising PSA in the face of hormonal therapy referred to here as Stage D2.5. This patient may have a negative bone scan and no symptoms, yet he has progressive hormone refractory prostate cancer (HRPC).

Early Hormonal Therapy
The clinician and patient are thus faced with the challenge of this common and threatening stage of prostate cancer—biochemical failure (D1.5)—and its natural progression to the hormone refractory state (D2.5). Hormonal therapy can produce dramatic but relatively short-lived responses in metastatic hormonally sensitive disease (D2), and chemotherapy is showing promise in inducing significant responses in the refractory state. Is there any evidence that aggressive intervention such as hormonal therapy, with or without chemotherapy, can improve the outcome of patients with biochemical failure? The honest answer is no. However, these treatments have resulted in some impact in patients in stages of disease with similar characteristics.. And so the germane question then becomes, can any meaningful information be obtained from current trials that will aid in the decision of how to treat biochemical failure? Can hormonal therapy not only prolong time to progression but also extend life? There are a number of studies whose results indicate that early disease detection and/or early hormonal therapy extend life and may cure some patients. Studies that have evaluated early hormonal therapy include:

            VA studies

            MRC study

            Adjuvant radiation studies

            ECOG/Intergroup D1 study

            Each of these will be discussed in detail. Several of these studies show that early is better than late.

VA and MRC Studies
Two studies suggest that early therapy in stage D2 (M+) disease achieves the goal of prolonging life. These are the VA studies and the recently completed MRC (Medical Research Council) clinical trial. In the VA studies (VACURG Study II) of men with locally advanced and metastatic disease, 1 mg of diethylstilbestrol (DES) was slightly more effective than a toxic dose of 5 mg, an ineffective dose of 0.2 mg or a placebo.

Figure 1-insert here
Similarly, the MRC study revealed a survival advantage to early therapy in locally advanced disease. The effects of immediate vs deferred therapy was evaluated in 987 asymptomatic patients in either Stage D2 or Stage C (T3) prostate cancer. Patients treated early exhibited a marked decrease in comorbid events, including pathologic fractures, spinal cord compression, ureteral obstruction and extraskeletal metastases. The reduction in these disease related events is enough evidence to justify the use of early therapy. However, additional support for early therapy comes from survival data. Patients treated with early therapy exhibited a small but significant increase in rates of both overall survival and prostate cancer-specific survival

In patients with locally advanced nonmetastatic disease, the benefit was even more pronounced. The survival benefit increased over time; the survival rate at 10 years of patients receiving early therapy was almost twice that of patients receiving delayed therapy Figure 2-insert here.

Thus, the MRC study supports the concept of early hormonal therapy. There has been some criticism of this study because not all of the men had had bone scans, and therefore accurate staging was not performed. In addition, a few men never received treatment for their disease. Although these are legitimate concerns, they do not negate the important findings of this study.  . The results of the MRC study indicate that the disease state of the patient is particularly important. The survival benefit of early hormonal therapy was significantly greater for those with less advanced disease (nonmetastatic prostate cancer).

Stage D1-Positive Lymph Node Disease
The number of patients who present with positive lymph disease is decreasing. This is attributed to early detection efforts and better patient selection for local therapies. There has been debate regarding the benefit of early hormonal therapy in patients who are found to have positive lymph node disease as the only site of spread of their prostate cancer. Most prostate cancers will spread to the pelvic lymph nodes as the first step of their progression. In many cases this spread precedes bone disease. To address this question, a cooperative group trial was implemented comparing immediate vs deferred hormonal therapy in men who had lymph node involvement and had had a radical prostatectomy and pelvic lymphadenectomy. This intergroup clinical trial demonstrated marked improvements with immediate hormonal therapy vs delayed in both prostate cancer-specific survival (30.8% vs 4.3%) and progression (75% vs 18.8%)  Figure 3-insert here

This study, like the VA and MRC studies already discussed, shows a clear survival advantage resulting from early therapy. The tumor burden of these men is likely less than or at least equivalent to that of men who have stage D1.5 disease (PSA-only recurrence).

Neoadjuvant and Adjuvant Studies

With Radiation Therapy
Bolla and colleagues have provided documentation that the combination of hormonal therapy and radiation therapy is superior to radiation alone in the management of T3 prostate cancer.

In the Bolla study, 3 years of hormonal therapy in combination with 6-7 weeks of external beam radiation therapy (EBRT) resulted in a significant therapeutic benefit over radiation therapy alone. Estimates of survival after 5 years were greater following combined therapy vs EBRT (79% vs 62%). Furthermore, 85% of patients receiving combined therapy remained disease free, compared with 48% of patients receiving EBRT alone. Some have questioned whether radiation therapy contributed significantly to these outcomes and whether it is clinically necessary. Thus, a randomized trial is now underway in Canada to test the impact of hormonal therapy alone. This important trial will randomized men with locally advanced prostate cancer to hormonal therapy alone versus hormonal therapy and radiation therapy.

Another study, the RTOG 8610 trial, evaluated whether just 4 months of hormonal therapy with EBRT improved outcomes over radiation therapy alone for patients with T3 prostate cancer. This study used neoadjuvant (hormone therapy before radiation) and then adjuvant therapy after the radiation.  Initial analysis of results demonstrated improved local control (84% after combination therapy vs 71% after radiation alone) and freedom from biochemical failure and PSA recurrence (46% after combination therapy vs 21% after radiation alone) when just 4 months of hormonal therapy is added to the radiation. A recent analysis of this study of patients with long-term follow-up (after 5 and 8 years) also demonstrates a survival advantage in men with lower Gleason scores, as well as improved local control and a reduction in PSA recurrence.

Reduction in death rates from prostate cancer through screening
The death rates from prostate cancer have declined slightly in the past two years. Many researchers have attributed this to screening. This is likely the case, but it is unlikely that the improved survival is solely related local treatments alone. As already discussed, early hormonal therapy in combination with radiation have improved survival. Therefore part of this reduction in deaths may be attributed to earlier combination therapies.

Role of chemotherapy in early prostate cancer.
In breast and colon cancers, chemotherapy is not very efficacious when administered in the advanced metastatic setting, but does significantly improve survival when used earlier in the disease and in the adjuvant settings. Perhaps the same is true in prostate cancer. For this reason, the Southwest Oncology Group (SWOG) launched an International trial that will examine the role of chemotherapy in men at high risk of failing a radical prostatectomy. This is one of the most important clinical trials that are ongoing in prostate cancer. In this protocol, men at high risk of failing surgery are randomized to hormonal therapy for two years versus hormonal therapy and the chemotherapy drug, Novantrone ( mitoxantrone). This chemotherapy agent is well tolerated and is often referred to as “gentle chemotherapy”. The chemotherapy is admistered once every three weeks for 6 cycles. INSERT figure here

What men want from their prostate cancer treatment?
Several years ago in conjunction with the US TOO support group we did a survey of 1000 men asking them what they wanted from their prostate cancer treatments. The table below outlines their answers, and as can be seen, extending survival was the most important. The survey was published in USA Today.

Conclusions
Cancer is a collection of genetic changes, and the longer it is around the more genetic changes that occur. This statement is important not only in prostate cancer, but also in, most cancers. The longer it is around, the less responsive it is to treatments. In prostate cancer we have very effective treatments. Hormonal therapy produces dramatic responses in advanced disease but does not cure it. If parallels exist in prostate and breast cancer, then earlier treatment will result in improved survival. Chemotherapy can improve a patient’s quality of life when they are refractory to hormones (stage D3), but has not yet shown to improve life expectancy. As already mentioned, that is the same in breast cancer. But in breast cancer when chemotherapy was moved up to the adjuvant setting, then survival improved. The same finding occurred in colorectal cancer.

The trials described in this article all support a survival advantage or decrease in co morbid events when hormonal therapy is administered early. The advantage is more pronounced in patients with lesser tumor burdens. These results suggest that early hormonal therapy administered to patients with a rising PSA after failed local therapy might provide the same benefit. But how long should therapy be administered and what agents should be used? Could intermittent therapy be offered and expected to result in survival benefits? Should chemotherapy be considered in conjunction with hormonal therapy? There are many unanswered questions. Where clinical trials are available, patients should be encouraged to participate. The only way to answer these questions is through carefully conducted randomized clinical trials. Information on these trials is available through your doctor and on a number of websites. Two such sites are the xxxx and the Southwest Oncology Group website.

In the interim until the answers are known, I believe that hormonal therapy with or without chemotherapy should be offered to most patients with biochemical failure. Predicated on the exciting activity of newer forms of chemotherapy on hormone refractory disease, I believe that patients with stage D2.5 should also be offered these therapies. Patients at high risk of failing local therapies seem to benefit from early hormonal/chemotherapy.

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