Management of Locally Advanced Prostate Cancer
Management of Locally Advanced Prostate Cancer
Over the last 10 years, we have learned more about not only the natural history of untreated locally advanced prostate cancer but also the ways in which we can effectively modify radiation therapy to treat this disease. There are now sufficient data to suggest that patients with prostate cancer that is considered locally advanced (stages T2b to T4) have a propensity for the development of lymph node metastasis and occult distant spread. In these patients, there also is a recognized difficulty in controlling the disease locally with radiation, due to the bulk of tumor present and the surrounding dose-limiting, late-reacting normal tissues.
Although radiation oncologists have explored a wide variety of techniques to control bulky prostate tumors and have conducted elegant studies, we need to crystallize what we now know and use that knowledge to establish what is currently "standard therapy" for locally advanced disease.
Three general directions can be taken to improve local control by manipulating radiation therapy. These are:
1) Increasing the relative integral dose, or the dose delivered to the tumor vs the dose received by normal tissues. This is exemplified by the use of brachytherapy and proton-beam radiation techniques. It is also characterized by the increasing use of conformal external-beam radiation therapy, which, by reducing the margins around a tumor and conforming the radiation beam to the tumor, may actually allow higher doses of radiation to be given.
2) Shrinking the tumor prior to irradiation. It is well known that there is a dose-volume relationship in prostate cancer. As the tumor size or volume increases, so does the possibility of sterilizing that tumor. By using such techniques as hormonal cytoreduction, it is theoretically possible to reduce the tumor burden and improve the efficacy of standard photon irradiation.
3) Use of radiobiologic manipulation. This may be characterized by the use of (1) radiation sensitizers or protectors to enhance the effect of radiation at the tumor site vs the normal tissue site; (2) biologically active particles, such as neutrons or charged particles; or (3) various fractionation techniques that give a radiobiologically more effective dose to the tumor than to the normal tissue.
Can we, in 1996, begin to sort out what avenues of research we should continue to take and state whether the burden of proof has been fulfilled for any of these techniques? If we define "burden of proof" as having (1) theoretical relevance, (2) phase II data, (3) randomized phase III data, and (4) phase IV data focusing on improvement in the technique, we have a score card by which we can analyze these therapies.
Clearly, all the therapies listed above are based on sound theoretical principles and, to some extent, have been validated in phase II settings. However, the majority have not been subjected to rigorous phase III testing, and very few have undergone phase IV modification and evaluation.
Improving the Relative Integral Dose
Brachytherapy has theoretical advantages in terms of delivering more dose to the tumor by the implantation of radioactive material directly into it. The use of iridium-192 brachytherapy in locally advanced prostate cancer has been associated with an improved local control rate, as evidenced by an improved biopsy-negative rate after therapy. In addition, other phase II data have suggested a possible improvement in disease-free survival with this modality, as compared with historical data. To date, however, no phase III trials have compared brachytherapy to external-beam irradiation.
Probably the most commonly used technique today is conformal-beam radiation therapy. Its purported advantages include (1) a reduction in the level of toxic effects and (2) the ability to deliver higher doses by providing a more conformed pattern of radiation to the tumor, and thereby effect better tumor control. As yet, no long-term phase III clinical trial data have evaluated this form of therapy, but phase II data suggest that acute toxicity may, in fact, be reduced. Probably the best form of "conformed" radiation is proton irradiation, which, by virtue of its physical characteristics within tissue, affects only a very tight margin around the tumor volume. Unfortunately, data from the only randomized phase III trial of proton irradiation, conducted by the Massachusetts General Hospital group, were negative.
Reducing the Tumor Volume
This technique is best exemplified by the use of hormonal manipulation prior to external-beam radiotherapy. Good theoretical data support this technique; notably, the endocrine sensitivity of prostate cancer and the ability to achieve local control with hormonal manipulation alone. Several phase II studies have demonstrated that a wide variety of hormonally active agents can result in improvements in digitally evaluated local control. Two phase III data sets, from the Radiation Therapy Oncology Group (RTOG) and the Canadian Uro-Oncology Group, respectively, have evaluated the use of hormonal manipulation as neoadjuvant therapy prior to irradiation in randomized multicenter settings. Both of these studies have demonstrated an improvement in disease-free survival, as well as in the rate of histologically evaluated local control. The data from both of these randomized studies also have shown that the use of neoadjuvant hormonal manipulation is not associated with a significant increase in toxicity.
Radiobiologically Modified Techniques
Although altered fractionation techniques have been used in radiation oncology, they have not been evaluated in a systematic way in the treatment of prostate cancer. Perhaps the most important set of studies evaluating a modality with differing radiobiologic characteristics in normal and tumor tissue has focused on neutron irradiation. This technique has the theoretical advantages of being more effective than photon irradiation in situations of hypoxia and having less cell cycle dependency.
There are now two phase III trials conducted by the RTOG with data at 10 and 5 years, respectively, that can be used to evaluate this technique. The first study compared, in randomized fashion, a mixed neutron beam to photon-beam therapy alone in locally advanced prostate cancer. This study demonstrated superior disease-free and overall survival for patients treated with mixed-beam therapy, as compared with those treated with proton beam therapy alone. To date, this is the only study that has demonstrated a survival advantage based on a change in local therapy alone.
The second study compared a "pure" neutron beam to photon irradiation alone. To date, this study has not demonstrated an improvement in overall survival for those treated with neutron-beam therapy. However, it has shown a significant difference in disease-free survival. Although initial neutron irradiation studies showed an increased toxicity secondary to the type of collimation used, new phase IV data looking at multileaf and multirod collimation together with three-dimensional treatment planning have demonstrated that neutrons can be given with a toxicity profile similar to that of photon irradiation.
At present, we believe that we can begin to make some fairly definitive statements about the management of locally advanced prostate cancer with external-beam radiotherapy:
1) External-beam photon irradiation does not provide adequate control in this disease setting, as compared with some of the new modalities.
2) There are now sufficient phase III data to recommend hormonal cytoreduction plus photon-beam radiation or neutron-beam radiation as validated techniques in this clinical situation.
3) Conformal-beam external irradiation and brachytherapy have shown encouraging results in phase II trials but must be validated by randomized phase III data.
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