THE "NEW" PROSTATE CANCER INFOLINK

There are several recent reports that address factors specific to the combination of hormone therapy with radiation therapy in the management of prostate cancer, so we thought it would be helpful to offer a topical update.

The use of hormone therapy before, during, and after radiation therapy is certainly of value in optimizing the impact of radiation therapy on carefully selected patients with localized and progressive forms of prostate cancer. However, hormone therapy comes with significant adverse effects on patients. And, in general, the longer hormone therapy lasts, the greater the impact of these adverse effects, implying that patients should want to be on hormone therapy only as long as is absolutely necessary to get the best therapeutic response to treatment with the fewest adverse events possible. We are getting better at understanding how to make these types of judgment call — even though we don’t (yet) have definitive answers for every situation.

Let us look first at the role of neoadjuvant hormone therapy in combination with radiotherapy for management of localized disease.

Earlier this year, Crook et al. published the final report of a randomized, multi-center Canadian trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer. According to this report, “A longer period of [neoadjuvant hormone therapy] before standard-dose [radiation therapy] did not alter the patterns of failure when combined with 66-Gy [radiation therapy]. High-risk patients in the 8-month arm had significant improvement in the 5-year disease-free survival rate.” In other words, overall it didn’t make any difference whether these patients got 3 or 8 months of hormone therapy prior to radiation, but a longer period of hormone therapy did seem to improve the outcome significantly for patients with high-risk disease.

More recently, however, the same group of authors has reported that, following a re-analysis of data from this Canadian trial, the critical factor that predicted response to therapy was actually the PSA level immediately following hormone therapy rather than the period of the hormone therapy. Their data now show that patients whose PSA was ≤ 0.1 ng/ml after neoadjuvant hormone therapy and before initiation of radiation had a better biochemical recurrence-free surivival time than patients whose PSA was > 0.1 ng/ml after neoadjuvant hormone therapy. The authors now state that the critical prognostic determinants of response to neoadjuvant hormone therapy + conventional radiotherapy arethe initial PSA level before hormone therapy, the Gleason score, and the PSA level after neoadjuvant hormone therapy. The actual duration of therapy seems to be irrelevant.

These most recent results make perfect sense to The “New” Prostate Cancer InfoLink, and they correlate well with the idea that — in general — hormone therapy should be customized to address actual patient response rather than just putting patients on hormones and leaving them on these drugs for long periods of time. In their abstract summarizing the results of this second paper, Alexander et al. make the important point that, “Biochemical response to neoadjuvant ADT before RT, not duration, appears to be the critical determinant of benefit in the setting of combined therapy. Individually tailored ADT duration based on [pre-RT, post-hormone] PSA would maximize therapeutic gain, while minimizing the duration of ADT and its related toxicities.”

What about patient age in man with localized disease? How does that impact the decision process? We are probably all aware that the U.S. Preventive Services Task Force has recommended against screening men over 75 for prostate cancer.

Ngyuen et al. have just reported data from a study designed to explore whether older, healthy men could benefit from aggressive prostate cancer treatment. Their study included 206 men with intermediate to high risk, localized prostate cancer randomized to receive 70 Gy of radiation (RT) or RT plus 6 months of androgen suppression therapy (RT+AST). Of the 78 healthy men in this study (i.e., with mild or no comorbidity), 78 were older than the median age of 72.4 years. In this subgroup, RT+AST was associated with a significantly lower risk of death and with a significantly lower 8-year mortality estimate. Conversely, among men with moderate or severe comorbidity, 24 were older than the median age of 73, and in this subgroup, treatment with RT+AST was associated with a significantly higher risk of death. In other words, in older men with mild or no comorbidity, treatment with RT+AST was associated with improved survival compared with treatment with RT alone, suggesting that healthy older men may derive the same benefits from prostate cancer treatment as younger men.

Now what about adjuvant therapy in combination with radiation for locally advanced disease?

In 1997, Bolla et al. originally published data from an EORTC study showing that, for European patients diagnosed with locally advanced prostate cancer (high-risk T1-2 and T3-4N0-1M0 tumors), external beam radiation therapy + an adjuvant  LHRH agonist for 3 years clearly increased the probability of progression-free and overall survival compared to external beam radiation therapy alone. Additional data from European and American studies have shown similar results. Basically, 2-3 years of hormone therapy, initiated at the same time as radiotherapy, substantially improves survival, but it comes with serious adverse effects that may also impact the potential survival of patients and certainly impacts their quality of life.

In 2008, Horwitz et al. reported data from a US study (RTOG 92-02) showing that, at 10 years of follow up, RT + extended adjuvant hormone therapy (i.e., hormone therapy for 28 months) increased  the probability of disease-free survival and disease-specific survival, and lowered the probability of local progression, distant metastasis, and biochemical failure compared to RT + short-term hormone therapy (hormone therapy for just 4 months). In this study, overall survival was only increased for patients with a pretreatment Gleason score of 8-10. In this study eligible patients had T2c-T4 prostate cancer with no lymph node involvement beyond the pelvis and a PSA level < 150 ng/ml.

We now have data from EORTC 22961, in which Bolla et al. have investigated the duration of radiation + neoadjuvant hormone therapy among patients with clinical stage T1cN1-2M0, T2a-bN1-2M0, and T2c-4No-2M0 and a PSA of up to 150 ng/ml. In this study, all patients received RT + 6 months of combined androgen deprivation ( an LHRH agonist + an antiandrogen) and were then randomized to receive a further 30 months years of LHRH agonist therapy (without the antiandrogen) or no further hormone therapy. Their results demonstrate a statistically significant overall and prostate cancer-specific survival benefit for long-term hormone therapy at 5 years.

Finally, in a completely separate study, Widmark et al. has shown that radiotherapy + hormone therapy offers a clear survival benefit compared to hormone therapy without the radiation in patients with locally advanced disease, so there can be no doubt that both radiation and hormone therapy are required to optimize the survival benefit.

So where does all of this leave us?

The “New” Prostate Cancer Infolink thinks that we can now be very clear about some things and less clear about others, as follows:

• In men with clinically localized prostate cancer, the greatest benefit of hormone therapy is clearly associated with the ability of neoadjuvant hormones to reduce the PSA level to < 0.1 ng/ml prior to radiation therapy, and so hormone therapy will be most effective if it accomplishes this prior to initiation of radiation.
• This is likely to be true even in men older than 75 years of age if they are healthy and have no of minimal comorbidity.

The question this raises is, how long should homeone therapy be continued prior to initiation of radiation if the PSA does not go down to < 0.1 ng/ml. As yest we don’t appear to have an answer to this question, but a duration of hormone therapy of > 1 year would seem fairly pointless.

• In men assumed to have locally advanced prostate cancer, based on the data available so far, the greatest benefit appears to accrue to men who receive 2-3 years of adjuvant hormone therapy. However, the results of the Canadian trial would seem to suggest that we may not have analyzed the available data correctly (as yet).

Given the data from the Canadian trial of neoadjuvant therapy, one is tempted to ask the following questions about the studies in patients with locally advanced disease:

• Would neoadjuvant hormone therapy to reduce the PSA levels of patients to < 0.1 ng/ml improve the probability of long-term survival?
• In men with locally advanced disease whose PSA can be reduced to < 0.1 prior to RT, is extended hormone therapy beneficial compared to either no further hormone therapy or additional short-term hormone therapy?
• In men with locally advanced prostate cancer whose PSA can be reduced to < 0.1 prior to RT, is intermittent hormone therapy appropriate for 2-3 years compared to either no further hormone therapy or additional short-term hormone therapy?
• Do other known risk factors (e.g., Gleason score > 7; PSA > 20 ng/ml at baseline) change any of these probabilities?
• In men with a rising PSA after surgery, should neoadjuvant hormone therapy be a standard strategy to reduce the PSA to < 0.1 ng/ml before initiation of radiation? And in whom is such treatment apprpriate — only men with a PSA doubling time of < 12 or 15 months?

Remember the goal of adding hormone therapy to radiation. It is to give the hormone therapy only as long as is absolutely necessary to get the best therapeutic response to treatment with the fewest adverse events possible. Despite the fact that we have learned more than we knew, we clearly still have a ways to go!

Filed under: Management, Treatment | Tagged: adjuvant, androgen deprivation, hormone therapy, neoadjuvant, radiotherapy |