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Radiation Therapy: Inside and Out

Significant progress has been made in the technique of radical prostatectomy surgery to the point that it has been dubbed the "Gold Standard" for primary prostate cancer therapy, by urologists. However, the options for treatment do not begin nor end there.

Radiation therapy has long been used successfully to treat the disease and has equally made significant strides in the improvement of technique to the point where the "success" rate compares very favorably with radical surgery.

To help us navigate through the available choices is Dr. Mack Roach III, Professor in the Department of Radiation Oncology and Urology at the University of California San Francisco Comprehensive Cancer Center. Dr. Roach is also a skilled clinician who practices what he teaches.

VS: Dr. Roach, I think that it would be helpful to have an understanding of the historic progression in radiation oncology and its techniques. 

MR: Radiotherapy as the primary treatment of choice for prostate cancer, dates back nearly 100 years with Brachytherapy. This was replaced by External Beam Radiotherapy in the 1950's. The effectiveness of this modality was limited by the effective depth of penetration of the radiotherapy waves in reaching the prostate gland and tumor site; increasing dosage to achieve better penetration often resulted in "burns" of the skin. The introduction of the linear accelerator at Stanford under the direction of Dr. Bagshaw in the late '60's heralded the beginning of modern high energy teletherapy (shooting radiation at a distance) in treating prostate cancer. In contrast, the modern radical retropubic prostatectomy, pioneered by Dr. Patrick Walsh at Johns Hopkins, did not appear until the 1980's and its use and popularity increased dramatically with concomitant anesthesiological advances. 

VS: If we focus for a moment on external radiation techniques, what are the basic and qualitative differences among conformal 3-D x-ray based radiation therapy and proton beam therapy?

MR: All of these modalities are variations of teletherapy using electro-magnetic radiation to treat the disease. The differences occur in the matter of accuracy in delivery of the radiation to the tumor site. In the '80's, the CT (cat)Scan enabled the radiation oncology team to better image the pelvic anatomy. In the late '80's, improvements in computer software gave three-dimensional re-construction to the CT Scan images in order to achieve better radiation dosage distribution. The first FDA approved software refinements came from Dr. Alan Lichter's group at the University of Michigan. Today we see more than a dozen various software providers with tools to help enhance the imaging and delivery capability.
The general standard, state-of-the-art treatment method is 3-D conformal beam therapy as practiced at most medical centers. Variations of this technique include the IMRT (intensity modulated radiation therapy), which is the next generation of 3-D conformal therapy that uses a computer-controlled probe to alter the shape of the radiation beam to focus on a smaller area of the tumor. This enables the physician to vary the dosage to differing parts of the prostate to kill the cancer while minimizing damage to the surrounding healthy tissue. A disadvantage to this technique is that, in some cases, the cancer may be more extensive than can be covered by the narrow beam and may be better covered by the broader spectrum of the regular 3-D beam. Additionally, because the prostate does not remain "fixed" in a position, i.e. breathing, volume of urine in the bladder, etc. can potentially move the prostate and tumor out of the desired target area. There are techniques available which can address this situation and an experienced radiation oncologist can anticipate the possibility.
Proton beam therapy in theory has advantages over X-ray based radiotherapy because the edges of the beam are more tightly focused (less fuzziness) which should enable better tumor targeting; however, the advantages decline with the increased number of beams. Effectiveness of this procedure cannot be quantified because it is in limited availability because of the cost to acquire the equipment (approximately $104,000,000). The cost of maintenance and operator training are also factors which translates into a higher cost to the patient with no  proof of improved survivability or minimized side effects.

VS: A core fear that many individuals have is that they can get too much radiation, get burned by the treatment; how does the radiation oncologist determine dosage for each patient?

MR: While that potential still exists, it is greatly reduced by the systems and procedures that emphasize a customized therapy plan based on the patient's anatomy. The experience of the team in treating the disease using the appropriate radiological technique reduces the risk as well. The key factor in assuring effective treatment is not only total dosage, but where you put it.

VS: In conversations with patients who have had external beam therapy, a seemingly common complaint is fatigue; is this an expected side effect and are there others which can occur?

MR: We really don't know why fatigue occurs. Fatigue occurs as does depression. It's our belief that it is in part a psychological phenomenon rooted in the process of diagnosis and treatment. When a patient gets that first word that he has prostate cancer, it starts a prolonged increase in adrenaline production which remains at high levels until the treatment is completed. The letdown (or relief) that occurs post-treatment could manifest itself physically as depression because the presence of the adrenaline has been removed. We note this effect with seed implant therapy as well. Another reinforcement of the psychological hypothesis is the fact that depression often causes fatigue. Many patients exhibit a depressive state until they decide on, and complete, a treatment plan. Additionally, some patients may experience a burning sensation during urination as well as stiffness in the hips.

VS: Successful outcome of any primary therapy for prostate cancer is determinant on a proper diagnosis which indicates a high degree of contained disease within the capsule. Does external beam radiation provide a greater margin for error in treating those cases wherein extracapsular escape is suspected?

MR: Successful outcomes depend on the appropriate and accurate staging of the patient and his disease risk. In a low risk patient, where all indicators (PSA level, Gleason Score, imaging, etc.) point to organ-confined disease, seed implants may provide an effective therapy and the addition of external beam therapy is not  needed. In some cases, a revenue issue may be a factor and external beam treatment alone may also provide a cost effective option. In the higher risk patient, external beam therapy is added affording best chance for cure. It should also be noted that, in those instances where the provider may not have experience with brachytherapy, external beam therapy may be the desired choice. Where high risk is noted, the potential to use brachytherapy (seed implants) is available, but with a greater risk for lymph node involvement external beam should be added. In these situations, external beam radiation is used prophylactically to cover the lymph nodes.

VS: There have been several studies that support using hormonal therapy prior to radiation; yet there is a great deal of discussion as to the length of time and whether or not to continue the hormones after radiation. What is your take on the issue?

MR: There have been many studies, however two of the most relevant to hormonal use as a neoadjuvant (chemical agent used in conjunction with a primary treatment) therapy: Dr. Mark Soloway's work showing that hormonal therapy prior to surgery did not result in a survival benefit and Dr. Michel Bolla's study which showed an increase in survival for men undergoing XBRT. Editor's Note: See Study
We can say that hormonal therapy, depending on the patient, will help some people live linger; those patient categories can be defined as follows:
Low Risk Patients: Gleason score of 2 to 6; PSA less than 20; staged at T1-2; within this group we would expect a nearly 100% survival rate at 10 years post therapy. Using hormonal therapy would provide no benefit to survival and increases toxicity
Intermediate Risk Patients: Higher Gleason scores and PSA levels; 5 to 20% risk of mortality at 10 years post therapy. Hormonal therapy in this situation would improve the effectiveness of the radiation therapy. We would also seek a short term utilization of the hormones from a few weeks before start of radiation or either during the course of radiation treatment, with cessation of hormonal use at the conclusion of the radiation treatment. In these situations the risk of lymph node involvement is approximately 15%; short term hormone therapy with radiation to the lymph nodes reduces the risk of recurrence.
High Risk Patients: With more advanced stage disease; long term use of hormonal therapy would have benefit past the period of radiation therapy in surpressing distant microscopic disease. 

VS: So far we've talked about external techniques; what about the variations of minimally invasive techniques such as brachytherapy, seeds with conventional XBRT and MRSI which uses an endo-rectal component?

MR: We now have 10 and 15 years data that support brachytherapy as an effective alternative to surgery for treatment of locally confined disease with fewer side effects for those patients for whom it is best indicated. Although the patient may meet these criteria, they still may not be candidates for seed implants because the prostate may be too large, they may be on anti-coagulant medication, or they may be too obese. The two types of radioactive seeds used are: Iodine-125 based ones will have a half-life of 60 days and be active for 6 months; Palladium-103 will have a greater dose intensity with a 17 day half-life and an active phase of two months. Additionally, there has been usage of High Dose External Radiation done in conjunction with the seed implants to maximize the cancer killing effectiveness, but no reliable supporting studies show any advantages for survival.

VS: Again a major concern with the implanted seeds is the "radioactive" factor; are there specific precautions that are necessary with this procedure?

MR: We recommend that patients wear condoms during sex for the first couple of weeks after implantation in the rare situation when a seed may be passed through ejaculation. Pregnant women, small children and small animals should not sit in the lap of the patient unprotected. Your doctor may suggest use of a lead apron or recommend the time that distance should be maintained.

VS: We've made some assumptions as to radiotherapy for organ-confined disease; are there any instances where you would not recommend radiation as the primary therapy?

MR: While there will always be exceptions, generally radiation would not be the primary therapy where urinary system problems exist, such as a high IPBSS or AUA Systems score. Additionally if the patient has a large TURP defect (not enough viable tissue because of the hole in the prostate created by a previous transurethral radical prostatectomy), an enlarged prostate with pubic arch interference greater than 50 cc's or prior radiation in the area such as for rectal cancer. There are many studies which show that urinary flow problems can be made worse through radiation.

VS: In those instances where we see a return of the cancer after primary therapy, either surgery or radiation, radiation is usually seen as the logical treatment; however, given that the prostate bed is usually the prime target for radiation, how can we be sure that that is the only site of recurrence?

MR:  We can't always be certain. A recent study done by the University of California examined post-prostatectomy patients who exhibited a rising PSA. A biopsy was done and over 50% of the patients had positive results for recurrent disease. Of this group, previous ultrasound examination found indications of suspect areas in 90% of the instances. This suggests that local focal recurrence can be identified and effectively treated. We know that hormonal therapy is not curative, so we would look to radiate the area or, in some cases, use seed implants. Where radiation was the primary therapy, a salvage prostatectomy would be another option.

VS:  In advanced stage disease one of the main quality-of-life issues is PAIN. How does radiation compare with pain medications in dealing with this issue?

MR:  Drugs work against the cells that destroy bone. Cancer cells stimulate ostroclasts that "eat" bones and the metastasis to the bone produces pain as the bone is deteriorating. We have done randomized trials with Stage IV patients using radiation therapy of 800 rads (1 dose) versus 3000 rads (10 doses) to treat the pain from bone metastases. Our study shows that the cessation of pain and risk of recurrence is the same for both protocols. You can therefore achieve effective pain control at a lower cost and with a repeatable process.

VS: Looking at how we can increase the "certainty" of successful treatment, there have been two interesting studies which attempt to predict treatment failure: 1) the Pre-Treatment Nomogram developed by Memorial Sloan-Kettering and 2) the use of Ki67-LI staining for the MIB-1 antibody. How effective predictors are these as compared, let's say, to Partin Tables for radical prostate surgery?

MR: I don't use them in my practice; they have not been found to be helpful at all for me versus other measures that I use.

VS: What do you see in the future for radiotherapeutic techniques?

MR:  Computer controlled robotic delivery in real time that will improve targeting and effective dosage throughout the tumor.

VS:  Thank you, Dr. Roach, for your time in providing our viewers with this information and for your commitment to eradicating the disease. We look forward to speaking with you again in the future as more progress is made. 

 

 

 

 

 

 

 

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