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Michigan Oncology Journal Fall 98

Advances in Radiotherapy for Prostate Cancer

---Howard M. Sandler, M.D. and P. William McLaughlin, M.D.

The use of prostate specific antigen (PSA) for screening and the associated huge increase in newly diagnosed cases has led to significant changes in prostate cancer diagnosis and treatment. Radiotherapy for prostate cancer also has evolved dramatically and remains one of the most important treatment modalities for this common neoplasm.

External Beam Treatment
External beam treatment is the mainstay of prostate cancer radiotherapy (RT). Recent advances have led to the development of three-dimensional conformal therapy (3DCRT), a technique that uses modern imaging integrated with computerized planning and dose delivery to create radiotherapy plans that ensure accurate treatment of tumors and, simultaneously, minimize the radiation dose delivered to surrounding normal tissues. This technique, pioneered at the University of Michigan (1, 2), allows the delivery of higher doses of radiotherapy without increasing the risk of serious treatment-related morbidity. Early studies using 3D conformal therapy emphasized the low risk of side effects, as most serious side effects occur within two years. However, exciting recent reports from Michigan and elsewhere are beginning to reveal that higher doses are associated with better tumor control, as measured biochemically by serial PSA measurements after treatment (3, 4).

Data from University of Michigan reported this year at the American Society of Clinical Oncology meeting on the role of 3D conformal external beam therapy show that for early prostate cancer (T-stage T1 or T2, pre-RT PSA ² 10.0 ng/ml, Gleason score ² 7), the freedom from biochemical recurrence at five and eight years was 85 percent (SE 5 percent) at each time point. These data indicate that, at least out to eight years, freedom from biochemical recurrence is excellent and continues to be at least as favorable as reports from selected surgical series. The stability of the results between five and eight years also is encouraging regarding the durability of the response to RT, although longer follow-up is desirable.

Prostate Implants
An alternative treatment for localized prostate cancer is a prostate implant. In this procedure, radioactive seeds the size of a grain of rice are placed within the prostate. They emit radiation over a period of months. The penetration of the radiation is shallow, and thus the implants achieve the same goal as 3DCRT - high dose to the target and low dose to the surrounding normal tissues - by a completely different strategy.

Prostate implants changed significantly in the early 1980s. Ultrasound evaluation of the prostate by transrectal probe allowed detailed evaluation of the prostate and provided a technique to direct needles into specific locations for biopsy. Once this technology was developed, the concept of placing radioactive seeds using needles placed with ultrasound guidance emerged. The initial clinical results of ultrasound-guided permanent implants have been positive (5). The treatment results of early prostate cancer by implant compare favorably to both prostatectomy and external-beam radiotherapy. Some of the perceived advantages of the procedure are that it can be performed in one day as an outpatient and that there may be fewer severe complications than radical prostatectomy.

Although permanent implants show great promise, limitations and pitfalls remain. One limitation is that only the prostate is fully treated. The volume immediately adjacent to the prostate, which is encompassed during 3DCRT and may contain microscopic tumor, receives a limited dose of radiation. Therefore, it is critical that implants be offered to patients with a high probability of disease confined to the prostate, i.e. those with PSA ² 10, Gleason score ² 6, and unilaterally palpable disease, at most. Implants cannot be adequately performed if the prostate is too large (> 40-50 cc) and side effects may be increased if a previous TURP was performed. The most serious limitation, though, is the possibility of inadequate dose delivery to the prostate itself, despite ultrasound guidance.

University of Michigan studies have addressed the issue of inadequate dose delivery to the prostate (6, 7), and currently, additional seeds are placed in areas where lower dosing might occur and post-implant dose calculations are performed, using CT and 3D technology to locate each seed (up to 50-100) and to calculate the dose to the prostate. The prostate may swell due to the trauma of the implant, therefore a post-implant CT is performed two to four weeks later to allow for the prostate size to stabilize. If the actual dose as observed on the post-implant CT appears to be subtherapeutic, additional seeds are placed to correct the under-dosed region.

Future Directions
The relative benefit of 3DCRT or prostate implants, indeed the relative benefit of any therapy for localized prostate cancer remains unclear. The field of clinical prostate cancer research suffers from a paucity of well-designed comparative trials. The U-M is addressing this issue with the Department of Radiation Oncology's first intradepartmental phase III study: UMCC 9750, a randomized trial comparing 3DCRT to prostate implants. The study is open and accruing patients at all U-M faculty-staffed sites including University Hospital in Ann Arbor, Foote Hospital in Jackson, Ingham Regional Medical Center in Lansing, Providence Hospital in Southfield (and soon in Novi), and the Ann Arbor VA Hospital. Currently, implants are performed in Southfield, but plans are to build a system-wide prostate brachytherapy program this year.

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References
1. Lichter AS, Fraass BA, McShan DL. Recent advances in radiotherapy treatment planning. Oncology. 2:43-54, 57, 1988.
2. Sandler HM, Perez-Tamayo C, Ten Haken RK, Lichter AS. Dose escalation for stage C (T3) prostate cancer: minimal rectal toxicity observed using conformal therapy. Radiother Oncol. 23:53-54, 1992.
3. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer [see comments]. International Journal of Radiation Oncology, Biology, Physics. 41:491-500, 1998.
4. Pollack A, Zagars GK. External beam radiotherapy dose response of prostate cancer. International Journal of Radiation Oncology, Biology, Physics. 39:1011-1018, 1997.
5. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer. 80:442-453, 1997.
6. Narayana V, Roberson PL, Winfield RJ, Kessler ML, McLaughlin PW. Optimal placement of radioisotopes for permanent prostate implants. Radiology. 199:457-460, 1996.
7. Roberson PL, Narayana V, McShan DL, Winfield RJ, McLaughlin PW. Source placement error for permanent implant of the prostate. Medical Physics. 24:251-257, 1997.

 

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