95 RADIOTHERAPY FOR LOCALIZED PROSTATE CANCER

extremely favorable despite the fact that it includes Some larger tumors, less well differentiated tumors and pretreatment pSA greater than 20 ng./ml. The implant dose and the selection of radi- ation Source ("'1 or palladium) are based on speculative tumor factors, and the external beam treatment is a simple, 10 x 10, 4-fie1d box without noting special concern for protecting normal tissue. Median followup is not given but it is about 36 months SO that 5-year projections of outcome are preliminary estimates,

N o justification based on outcome or patterns offailure is made for the use of a combined approach in the most favorable patients (Tlc, T2a-b, PSA less than 10 ng./ml. and Gleason 6 or less than 6) compared to the more common single treatment with prostatectomy, external beam or implant alone in the less favorable grouping. The authors cite the Memorial Sloan-Kettering experience with freehand implants as an example of poor results with implant only (reference 4 in article.). However, the more modern excellent results of Ragde et al using ultrasound guided implants alone in select favorable pa- tients iirv not mentioned.' The authors also incorrectly cite the series of Stiimry r t a1 as an example of poor results with external beam, whcm it rrpresents poor results in patients with poor prognostic charnctrristics (reference 7 in article) and is not consistent with rcwilts of others.2 .I

Prctreiitment PSA level and Gleason score are not predictors of outcome. and stage (T3) is borderline significant, which is presum- ably ii result of excluding the node positive cases and reemphasizes tlw fiivornhlc. nature of this series. A confusing end point, treatment sucrcss. is used and is defined as PSA nadir 0.5 ng./ml. or less. The sourrts of this PSA level is Critz et al, which also shows along with others that some patients with PSA nadir greater than 0.5 ng./ml. are long-term cures (references 10 and 11 in article). The end point of biochemical failure is also used, which is similar to the end point in common usage.

Morbidity is not reported on any existing scale in common use for irradiated patients, and the gastrointestinal and genitourinary mor- bidity is clearly excessive compared to 3-dimensional (D) conformal radiation therapy, prostatectomy or previous reports of implant alone.1.5-6 Comparing our morbidity with 3-D conformal radiation therapy to the present series as example, rectal bleeding occurred in 21% (3-D conformal radiation therapy 15%), urinary retention, fis- tula, stricture and incontinence in 7.2% (3-D conformal radiation therapy 1% ), rectal wall breakdown in 0.5% (3-D conformal radia- tion therapy O S ) , and colostomy and urinary diversion in 6 of 212 patients (3-D conformal radiation therapy 1 colostomy in the last 1,000 patients.). Clearly, this is a technology looking for an applica- tion and this is their carefully reported experience. The authors note the critical need for quality assurance before and after the implant. Careful documentation of this approach is appropriate as the appli- cation of this technique to all T1 to T3 cases is investigational.

Single institution treatment programs rather than prospective randomized trials will continue to dictate what treatment is given to prostate cancer patients with various pretreatment prognostic char- acteristics. As long as we are not burdened by knowing which of the several options are better in a given patient, we will continue to pursue our individual prejudices in recommending treatment and devising new combinations, or the patient with a smaller database of useful information will make the treatment method decision among prostatectomy, 3-D conformal radiation therapy and implants. Novel approaches. such as presented in this article will be used by some institutions without a basis in comparison, while their value will await long-term results.

Gerald E . Hanks Department of Radiation Therapy FOX Chase Cancer Center Philadelphia. Pennsylvania

1. Rag&. H., Blasko, J. C., Grimm, P. D., Kenny, G. M., Sylvester, J . E., Honk. D. C., Landin, K. and Cavanough, w.: Interstitial iodine-125 radiation without adjuvant therapy in the treat- ment of clinically localized prostate carcinoma. Cancer, 80: 442. 1997.

2. Hanks, G. E., h e , W. R. and Schultheiss, T. E.: Clinical and biochemical evidence of control of prostate Cancer at 5 Years after external beam radiation. J. Urol., 154: 456, 1995.

3. Zagam, G . K,, Sherman, N. E. and Babaan, R. J.: Prostate specific antigen and external beam radiation therapy for Pros- tate cancer. Cancer, 67: 412, 1991.

4. &itman, A. L., &en, J. J., Shipley, w . u . , Willett, c. G. and Efird, J. T.: Radical radiation therapy in the management Of

prostatic adenocarcinoma: the initial prostate specific antigen value as a predictor of treatment outcome. J. Urol., 151: 640, 1994.

5. Hanks, G. E., Hanlon, A. L., Schultheiss, T. E., Freedman, G., Hunt, M., Pinover, W. and Movsas, B.: Conformal external beam treatment of prostate cancer. Urology, 50: 87, 1997.

6. Pound, C. R., Partin, A. W., Epstein, J. I. and Walsh, P. C.: Prostate-specific antigen after anatomic radical retropubic prostatectomy. Urol. Clin. N. Amer., 24: 395, 1997.

REPLY BY AUTHORS

The purpose of combined brachytherapy and external beam radi- ation is multifold. The first rationale is to respect the decades old experience of external beam radiation which was delivered using diligent blocking and 4-field techniques. Transperineal seed implan- tation in general was performed before external beam radiation and served as the boost or cone down in lieu of what would otherwise be a smaller external beam radiation field. The second rationale was to escalate the dose of radiation while not abandoning therapy with a known track record and benefit. This approach maintained the e f i - cacy of external beam radiation therapy while exploiting dose esca- lation that could be achieved with what many consider to be the ultimate in conformal therapy for prostate carcinoma, that is radia- tion seed implantation.

Some authors have criticized selection criteria in that select high risk patients are evaluated for lymph node metastases before the institution of therapy. Our point is that radiation should not be used indiscriminately, and patients who have a high risk of metastatic cancer to lymph nodes should be made aware of it and the risks, benefits and alternatives before institution of localized therapy. It is considered inappropriate to offer localized field radiation to patients with lymph node metastases, and the literature does not support extended wide field pelvic irradiation for lymph node metastases. A patient with positive lymph nodes may not desire the diminished potential benefits of localized therapy. I t is only for that reason, that is the institution of most appropriate therapy, that this high risk group of patients were evaluated surgically before radiation. In fact, only 6% of patients were excluded from this prostate cancer group. The vast majority (94%) did not undergo lymph node dissection, despite the preponderance of patients with PSA greater than 10 before treatment. Lymph node dissection was performed on patients who met 2 of 3 criteria of PSA 20 or greater, Gleason score 7 or higher and T2B or greater clinical lesion.

That our results are highly appealing should be obvious from the biochemical no evidence of disease rate. Our 5-year biochemical no evidence ofdisease rate using PSA 1.5 or less (reference 5 in editorial comment) was 79%. This rate compares exceedingly well to the conformal treated rate of 61% at 5 years of Hanks et al. They evaluated patients with PSA 0 to 9.9 and Gleason 6 or higher after conformal radiation, and had a 5-year biochemical no evidence of disease rate of 85% for localized and 704 for locally advanced cancer. At our institution patients treated with combined radiation seed therapy with pretreatment PSA 0 to 9.9 and Gleason 6 or greater had 88% biochemical no evidence of disease rate a t 5 years. The patients of Hanks et al with pretreatment PSA 10 to 19.9 had a 5-year biochemical no evidence of disease rate of 66'3 with localized and 44% with locally advanced disease, which compares to our 884 rate of all patients commencing therapy with PSA and Gleason score in the same range. Of those men with PSA greater than 20, Hanks et al report a 5-year biochemical no evidence of disease rate of 31 and 21%, respectively, compared to our 57% result in the same risk group. Thus, in our categories patients treated with combined modality radiation fared far superior to those undergoing external conformal radiation. This approach, when extrapolated upon thousands treated annually, could certainly favorably impact a difficult disease.

Treatment was exceptionally well tolerated and is becoming in- creasingly better tolerated with time. In the subsequent 538 patients treated after our series was reported the incidence of severe rectal irritation resulting in breakdown was 0.2%. This rate reflects the excellent tolerance of this procedure and technical aspects associated with it as well as the safety of aggressive radiation therapy per- formed by experienced hands. We evaluated patients with prostate biopsy after completion of therapy and found 86.1% with no evidence of cancer, which is far superior to conventional radiation and cur- rently reported conformal radiation results. Our updated results are even better. Urinary continence in patients who had not undergone

96 RADIOTHERAPY FOR LOCALIZED PROSTATE CANCER

transurethral prostate resection was 98% and sexual potency was maintained after radiation seed implantation in 6 2 5 of patients. Thus, combined external beam radiation therapy with prostate ra- diation seed implantation respects the known efficacy of external beam radiation while boosting radiation dose in a conformal manner using computerized preplanning, fluoroscopy and ultrasound during the procedure.

That our biochemical no evidence of disease rate of 7gr i at 5 years is 29.5% superior to the approach of Hanks et a1 should reassure men with localized prostate cancer that combined external beam radia- tion and transperineal seed implant in experienced hands yields a high rate of remission by PSA criteria as well as posttreatment negative pathological biopsy evidence. Even if lymph node positive

cases were included in our data, the results would still be superior to those reported for conformal therapy. Our approach was not to abandon a technique (external beam radiation therapy) that has a long track record of safety and efficacy for 1 with small conformal fields, but rather to combine it with super small conformal high dose radiation fields (radiation seed implantation) to produce what the investigators believe is the best of both. Combining the techniques resulted in a well tolerated treatment with a high degree of success. In general, the combined treatment approach is well tolerated, min- imizes duration of therapy compared to conformal or standard radi- ation, significantly boosts the radiation dose, and allows a high quality of life, sexual potency in most and urinary continence in nearly all men. Freedom of relapse remains high with this approach.