Quiescence in R3327-G rat prostate tumors after androgen ablation.

Androgen ablation is frequently used in conjunction with radiotherapy in the treatment of high-risk prostate cancer. Androgen ablation-induced cell kinetic changes could result in sub-additive (increased quiescence) or supra-additive (reduction in repopulation) interactions with radiotherapy. The cell kinetic changes were studied in R3327-G Dunning rat prostate tumors grown in vivo using double thymidine analogue labeling and flow cytometry, the terminal deoxynucleotidyl transferase-mediated nick end labeling assay for apoptosis, and measurements of tumor cell numbers. Tumors grown in intact and castrate male rats were continuously labeled for various periods of time with chlorodeoxyuridine and pulse-labeled with iododeoxyuridine 8 h before tumor removal. Androgen ablation resulted in a maximal reduction in labeling index (10 to 1.6%) and an increase in potential doubling time (Tpot; 6-42 days) within 3 days, which was related to a reduction in growth fraction (65% to <10%). In contrast, the length of S-phase was minimally altered (19 to 23 h). The response to androgen ablation involved little apoptosis and no necrosis, and Tpot was approximately the same as the tumor volume doubling time. Hence, the increase in Tpot was mainly the result of a shift to quiescence, and this shift occurred with minimal cell loss. Because quiescence is usually associated with radioresistance, these cell kinetic changes suggest that a sub-additive interaction may occur for some prostate cancers when androgen ablation and irradiation are given together.

Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy.

PURPOSE: To evaluate the therapeutic value of resection and the potential benefits of and indications for adjuvant and definitive radiation therapy for desmoid tumors. MATERIALS AND METHODS: We performed a retrospective review of 189 consecutive cases of desmoid tumor treated with surgical resection, resection and radiation therapy, or radiation therapy alone. Treatment was surgery alone in 122 cases, surgery and radiation therapy in 46, and radiation therapy alone in 21. Median follow-up was 9.4 years. RESULTS: Overall, 5- and 10-year actuarial relapse rates were 30% and 33%, respectively. Uncorrected survival rates were 96%, 92%, and 87% at 5, 10, and 15 years, respectively. For the patients treated with surgery, the actuarial relapse rates were 34% and 38% at 5 and 10 years, respectively. Among 78 patients with negative margins, the 10-year recurrence rate was 27%, whereas 40 margin-positive patients had a 10-year relapse rate of 54% (P = .003). Tumors located in an extremity also had a poorer prognosis than did those in the trunk. For patients treated with radiation therapy for gross disease, the 10-year actuarial relapse rate was 24%. For patients treated with combined resection and radiation therapy, the 10-year actuarial relapse rate was 25%. The addition of radiation therapy offset the adverse impact of positive margins seen in the surgical group. CONCLUSION: Wide local excision with negative pathologic margins is the treatment of choice for most desmoid tumors. Function-sparing resection is appropriate because adjuvant radiation therapy can offset the adverse impact of positive margins. Unresectable disease should be treated with definitive radiation therapy.

Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer.

PURPOSE: To determine the effect of radiotherapy dose on prostate cancer patient outcome and biopsy positivity in a phase III trial. PATIENTS AND METHODS: A total of 305 stage T1 through T3 patients were randomized to receive 70 Gy or 78 Gy of external-beam radiotherapy between 1993 and 1998. Of these, 301 were assessable; stratification was based on pretreatment prostate-specific antigen level (PSA). Dose was prescribed to the isocenter at 2 Gy per fraction. All patients underwent planning pelvic computed tomography scan to confirm prostate position. Treatment failure was defined as an increasing PSA on three consecutive follow-up visits or the initiation of salvage treatment. Median follow-up was 40 months. RESULTS: One hundred fifty patients were randomized to the 70-Gy arm and 151 to the 78-Gy arm. The difference in freedom from biochemical and/or disease failure (FFF) rates of 69% and 79% for the 70-Gy and 78-Gy groups, respectively, at 5 years was marginally significant (log-rank P: =.058). Multiple-covariate Cox proportional hazards regression showed that the study randomization was an independent correlate of FFF, along with pretreatment PSA, Gleason score, and stage. The patients who benefited most from the 8-Gy dose escalation were those with a pretreatment PSA of more than 10 ng/mL; 5-year FFF rates were 48% and 75% (P: =.011) for the 70-Gy and 78-Gy arms, respectively. There was no difference between the arms ( approximately 80% 5-year FFF) when the pretreatment PSA was < or = 10 ng/mL. CONCLUSION: A modest dose increase of 8 Gy using conformal radiotherapy resulted in a substantial improvement in prostate cancer FFF rates for patients with a pretreatment PSA of more than 10 ng/mL. These findings document that local persistence of prostate cancer in intermediate- to high-risk patients is a major problem when doses of 70 Gy or less are used.

Abnormal bcl-2 and pRb expression are independent correlates of radiation response in muscle-invasive bladder cancer.

The objective of this study was to determine whether the overexpression of bcl-2, a key protein governing the apoptotic response to radiation, adds to pRb status in estimating the propensity for radiation response in patients with muscle-invasive bladder cancer. Archival formalin-fixed, paraffin-embedded, pretreatment bladder tumor samples were available in 109 of 301 patients treated preoperatively with 50 Gy in 25 fractions followed by radical cystectomy 4-6 weeks later. Radiation response was assessed by clinical-to-pathological tumor downstaging or upstaging. Altered expression of bcl-2 (47% of 107 patients), p53 (56% of 109 patients), and pRb (30% of 98 patients) was assessed by immunohistochemical staining. Morphological criteria were used to calculate the percentage of apoptotic cells. bcl-2 staining correlated with tumor grade; all grade 2 tumors (n = 7) displayed normal bcl-2 expression (negative staining). No correlations between bcl-2 staining and pretreatment apoptosis levels, p53 staining, and pRb staining were observed. In terms of the radiation response parameters, univariate analyses revealed that bcl-2 overexpression was the only factor associated with upstaging. The main predictor of downstaging was the loss of pRb expression (negative staining). Multivariate logistic regression confirmed these findings and also showed that normal pRb expression (positive staining) was significantly related to upstaging. Patient outcome was adversely affected by bcl-2 overexpression, because these patients experienced significantly increased actuarial local failure rates. No difference in distant metastasis or survival rates by bcl-2 staining was seen. The strongest independent correlates of radiation response thus far identified in muscle-invasive bladder cancer are from bcl-2 and pRb immunohistochemical staining. The overexpression of bcl-2 and the normal expression of pRb seem to thwart the apoptotic response to radiation via independent mechanisms. Abnormalities in the expression of proteins that regulate apoptosis may prove to establish a molecular phenotype to characterize which patients should receive radiotherapy.

Androgen ablation in addition to radiation therapy for prostate cancer: is there true benefit?

Prostate cancer patients may now be identified as having a high risk of failing single-modality treatment based on pretreatment prostate specific antigen (PSA), Gleason score, and palpable stage. In particular, a PSA greater than 20 ng/mL portends a biochemical failure rate of 50% to 80% when radiation therapy, surgery, or androgen ablation is administered individually. A number of randomized trials as well as retrospective data show that failure rates are significantly reduced by combining androgen ablation and radiation. The improved results, however, are complicated by the ability to salvage radiation alone-treated patients with androgen ablation and the possibility of less effective salvage (or no effective salvage in the case of permanent androgen ablation) for patients treated with androgen ablation plus radiation. Thus, survival, which is obscured by high rates of intercurrent deaths in this elderly population, is the most important end point in such studies. Two randomized trials, one from the Radiation Therapy Oncology Group (RTOG) and one from the European Organization for Research on Treatment for Cancer (EORTC), of radiation therapy plus adjuvant (as opposed to neoadjuvant) androgen ablation have reported survival gains over radiation therapy alone. In contrast, one neoadjuvant trial from the RTOG failed to show a survival benefit when androgen ablation was added to radiation therapy. In this study, however, androgen ablation was administered for only 4 to 5 months, which may be insufficient. The weight of the evidence to date indicates a true benefit with androgen ablation plus radiation therapy over radiation therapy alone. There are clearly many unanswered questions concerning the optimal timing of androgen ablation and radiation therapy (neoadjuvant versus adjuvant), length of time that androgen ablation should be administered (6 months versus 3 years versus permanent), type of androgen ablation (total androgen ablation or not), and appropriate patient population (definition of high risk). The planned future clinical trials will address many of these issues; however, the full potential of this approach requires an understanding of the fundamental mechanisms involved.

Prostate cancer treatment with radiotherapy: maturing methods that minimize morbidity.

Technological advances in treatment delivery and planning have provided the backdrop for an unprecedented number of options in the treatment of prostate cancer with radiotherapy. The more common choices include classical external-beam radiotherapy, external-beam radiotherapy using three-dimensional treatment planning and conformal radiotherapy (3DCRT), ultrasound-guided transperineal implant monotherapy alone or in combination with external-beam radiotherapy, and intensity-modulated radiotherapy (IMRT) techniques. This chapter reviews the data from these methods with an emphasis on dose escalation, provides comparisons with prostate-specific antigen (PSA)-era radical prostatectomy series where appropriate, and highlights future initiatives designed to further improve outcome.

The prognostic significance of a single serum prostate-specific antigen value beyond six months after radiation therapy for adenocarcinoma of the prostate.

PURPOSE: The aim of this study was to define criteria for interpreting a single serum prostate-specific antigen (PSA) level measured at 6 months to 5 years after definitive radiotherapy for prostate cancer. METHODS AND MATERIALS: Two hundred and ninety-two patients with Stages A2 to C prostate cancer treated with radiotherapy only and followed up with multiple PSA determinations were studied. The patients were stratified into 5 PSA strata based on the highest PSA level recorded for each patient at 6 to 60 months after treatment. The PSA strata and the number of patients in each were: (a) PSA < or = 1 ng/ml, 114 patients; (b) PSA > 1, but < or = 2 ng/ml, 60 patients; (c) PSA > 2, but < or = 4 ng/ml, 48 patients; (d) PSA > 4, but < or = 10 ng/ml, 47 patients; (e) PSA > 10 ng/ml, 23 patients. Disease outcome specified as relapse, rising PSA profile or both was evaluated in each PSA stratum. RESULTS: The actuarial 3-year incidence of relapse in each PSA stratum was: (a) 5%; (b) 0%; (c) 12%; (d) 31%; and, (e) 84%. If the occurrence of a rising PSA profile was included as an endpoint then the incidence of relapse or rising PSA at 3 years in each PSA stratum was: (a) 5%; (b) 14%; (c) 45%; (d) 84%; and, (e) 100%. Patients with a highest late PSA value < or = 4 ng/ml had a 20% incidence of relapse or rising PSA at 4 years; patients with a highest late PSA value > 4 ng/ml had a 90% incidence of relapse or rising PSA at 3 years. CONCLUSION: A PSA level of 4 ng/ml is a good criterion for prognostication of a single PSA level obtained at 6 months to 5 years after radiotherapy. Patients whose PSA level in that time interval exceeds 4 ng/ml have a poor outcome.

Prostate-specific antigen as a prognostic factor for prostate cancer treated by external beam radiotherapy.

The potential prognostic significance of prostate-specific antigen (PSA) serum concentrations was evaluated in 171 patients with stages A2 to C adenocarcinoma of the prostate treated with external beam radiotherapy. After a median follow-up of 17 months, 12 patients sustained relapse of disease and PSA levels were found to be prognostically significant in three ways. (a) Pretreatment PSA level: none of 59 patients with a pretreatment PSA level less than or equal to 4 ng/ml relapsed to date and only one developed a subsequently rising PSA profile; 7 of 102 patients (7%) with a pretreatment PSA level in the range 4-40 ng/ml relapsed and 17 (17%) showed a rising PSA profile; 5 of 10 patients (50%) with a pretreatment PSA level greater than or equal to 40 ng/ml relapsed and six (60%) developed rising PSA values. The differences were significant and were maintained when patients were stratified by stage or grade. (b) PSA level at 6 months: for patients with pretreatment PSA levels in the range 4-40 ng/ml, a 6-month value greater than 2 ng/ml predicted a significantly worse outcome than a 6-month value less than 2 ng/ml. (c) Rising post-treatment PSA values: following a radiation-related nadir in PSA levels, 24 patients experienced rising PSA values and 8 (33%) relapsed at a median time of 5 months after onset of the rising values--a significantly higher relapse rate than observed in patients with non-rising PSA values. Whether the majority, or all, of the patients with rising PSA levels relapse, requires further follow-up. In conclusion, serum PSA levels are strong prognostic determinants of outcome following radiotherapy for prostate cancer and appear to add prognostic information independently of tumor stage and grade.

Stage I testicular seminoma: rationale for postorchiectomy radiation therapy.

The cases of 163 patients with Stage I seminoma of the testis treated by orchiectomy and adjuvant radiation therapy (XRT) were retrospectively evaluated to document outcome and to determine the prognostic significance of age side or primary, cryptorchidism, prior ipsilateral herniorrhaphy, status of the contralateral testis, history of prior testicular cancer, scrotal incision, postorchiectomy beta- human chorionic gonadotropin (BHCG) level, invasion of the epididymis, spermatic cord involvement, vascular invasion in the primary and mediastinal XRT. Of the prognostic factors evaluated, only spermatic cord involvement proved to be a significantly adverse factor. However, the true significance of cord involvement is unclear because the para-aortic regions were not irradiated in 2 of the patients in whom there was this finding, and in 1 of these there was failure in the retroperitoneum. Spermatic cord involvement was not a prognostically significant finding in patients whose para-aortic region was treated. For all 163 patients who underwent XRT, disease-free survival was 95% at 5, 10, and 15 years. Total survival corrected for intercurrent death was 97% from 5 through 20 years. Seven patients relapsed (4%) and 4 died of seminoma (2%). The XRT technique described is simple to implement and is extremely effective. Of 161 patients whose para-aortic region was irradiated, none developed subdiaphragmatic nodal recurrence. Only 1 patient developed acute leukemia. No patient developed any of the recognized delayed XRT-induced complications involving small bowel, large bowel, bladder, kidney, liver or spinal cord. The virtues and limitations of surveillance in Stage I testicular seminoma are discussed, and it is concluded that routine postorchiectomy XRT is the treatment of choice.

The role of radiation in stage II testicular seminoma.

This is a retrospective review of 62 patients with Stage II testicular seminoma treated either by initial radiation therapy (48 patients) or by platinum-containing chemotherapy (14 patients). For all 62 cases, disease-free survival from 2 to 20 years was 86%, uncorrected survival was 86% at 5 years and 83% at 15 years, and survival corrected for deaths from intercurrent disease was 90% from 2 to 20 years. There were no significant differences in outcome between the two treatment groups. An analysis of potential prognostic factors for the initial radiation therapy group and for the whole group revealed that age, site of primary, cryptorchidism, ipsilateral hernia repair, contralateral testicular atrophy, scrotal incision, elevated postorchiectomy beta-human chorionic gonadotropin level, epididymal invasion, spermatic cord involvement, and vascular invasion in the primary were not significant. However, bulk of abdominal disease was a prognostic factor. Patients with small-volume abdominal disease defined as nonpalpable disease or as a mass less than 10 cm in largest diameter accounted for two-thirds of the series and had a disease-free survival of 95% when treated with initial radiation therapy. Patients with bulky disease, either palpable or greater than or equal to 10 cm in diameter, had a disease-free survival of 64%. The relative roles of the two treatments in bulky abdominal disease are discussed, but in the absence of a prospective study it is not possible to definitively answer the question of which modality is best in this setting. In our series, the patients treated with platinum-containing chemotherapy fared as well as the primarily irradiated patients, but 71% of the former had palpable masses, compared with 22% of the latter. The chemotherapy-treated patients who relapsed were treated with radiation therapy for salvage, leading to a 100% survival corrected for intercurrent death. We have therefore elected to continue the policy of initial radiation therapy for small-volume (less than 10 cm) disease and platinum-containing chemotherapy for bulky disease (greater than or equal to 10 cm), with irradiation used for residual masses.

External beam radiotherapy dose response of prostate cancer.

PURPOSE: To determine the external beam radiotherapy dose response of palpable Stage T1-T4, mostly Nx, patients with adenocarcinoma of the prostate. METHODS AND MATERIALS: There were 938 men consecutively treated between 1987 and 1995 who had pretreatment prostate specific antigen (PSA) levels. Posttreatment failure was defined as disease recurrence and/or two elevations in PSA on consecutive follow-up visits. The radiotherapy technique consisted of a four-field box with a small four-field reduction after 46 Gy in 844 patients (total dose of 60-70 Gy) or with a six-field conformal boost after 46 Gy in 94 patients (total dose of 74-78 Gy). Neoadjuvant or adjuvant androgen ablation was not used in any patient. Median follow-up was 40 months. RESULTS: The mean and median radiotherapy doses for the entire group were 67.8 +/- 13.3 Gy (+/-SEM) and 66 Gy. The mean radiotherapy dose was higher in those who had Stage T3/T4 disease, Gleason scores of 8-10, or pretreatment PSAs of > 4 ng/ml. In general, patients with more aggressive pretreatment prognostic features were treated to higher doses; yet, those that relapsed or had a rising PSA were treated to significantly lower doses. Actuarial analyses were facilitated by dividing patients into three dose groups: < or = 67, > 67-77, and > 77 Gy. The actuarial freedom from failure rates at 3 years were 61, 74, and 96% for the low, intermediate, and high dose groups. Stratification of the patients by pretreatment PSA revealed that dose was a significant correlate of freedom from relapse or a rising PSA for those with PSAs > 4-10, > 10-20, and > 20 ng/ml. The only patients in which an improvement in outcome was not related to higher doses were those with a pretreatment PSA < or = 4 ng/ml. Dose was significantly associated with freedom from failure for Stage T1/T2 and Stage T3/T4 patients, as well as for those stratified by Gleason score. Multivariate analysis using Cox proportional hazards models showed that dose was an independent and highly significant predictor of relapse or a rising PSA. CONCLUSION: This retrospective review strongly indicates that radiotherapy dose to the prostate is critical to the cure of prostate cancer, even for favorable patients with pretreatment PSAs of > 4-10 ng/ml, Stages T1/T2, or Gleason scores of 2-6. Final confirmation awaits the results of our randomized trial.

Post-orchiectomy radiotherapy for stages I and II testicular seminoma.

PURPOSE: In 1984 the following changes were made in the management of testicular seminoma at The University of Texas M.D. Anderson Cancer Center: (1) abdominopelvic computerized tomography replaced the bipedal lymph-angiogram for evaluating retroperitoneal nodes; (2) elective mediastinal radiation was totally abandoned; (3) patients with abdominal adenopathy < 10 cm were classified as having Stage IIA disease. This report evaluates the impact of these management policy changes on disease outcome. METHODS AND MATERIALS: Between 1960 and 1991, 350 patients with Stages I or II testicular seminoma received post-orchiectomy radiation. The 241 patients treated prior to 1984 constitute our old series, and the 109 patients treated since then are our new series. The outcomes in the new series were compared to those in the old series. RESULTS: The distribution of patients by stage was Stage I, 282 (old series, 190; new series, 92); Stage IIA, 55 (old series, 39; new series, 16); Stage IIB, 13 (old series, 12; new series, 1). The freedom-from-relapse at 5 years correlated with stage: Stage I, 97%; Stage IIA, 87%; Stage IIB, 69%. Elevated post-orchiectomy chorionic gonadotropin levels or involvement of the spermatic cord were adverse for disease relapse in Stage I but not Stage II disease. Patients with Stage I disease fared extremely well in both series (freedom-from-relapse 97%); the outcome for patients with Stage IIA was significantly worse in the new series (5-year freedom-from-relapse 73% vs. 92%) because of a 20% actuarial incidence of apparently solitary left supraclavicular nodal relapse. Although elective mediastinal radiation in the old series prevented this failure pattern, such treatment appeared to significantly decrease the survival of patients older than 40 years. CONCLUSIONS: (1) Abdominopelvic computerized tomography scanning is adequate for the evaluation of abdominal lymph nodes in patients with seminoma; (2) Post-orchiectomy radiation to the para-aortic and ipsilateral hemipelvic regions remains the treatment of choice for patients with Stage I disease; (3) Patients with Stage IIA disease experience a 20% relapse rate especially in the left supraclavicular fossa and we recommend elective radiation to this site delivered concomitantly with para-aortic irradiation.

Serum testosterone levels after external beam radiation for clinically localized prostate cancer.

PURPOSE: To determine whether serum total testosterone levels change after external beam radiation therapy for localized prostate cancer. METHODS AND MATERIALS: Eighty-five men with clinically localized prostate cancer (T1-T3, N0/NX, M0) who underwent external beam radiation therapy without androgen ablation had pretreatment and 3-month posttreatment total serum testosterone levels determined by radioimmunoassay. Scattered doses to the testicles were measured with thermoluminescent dosimetry in 10 men. RESULTS: Pretreatment serum testosterone levels ranged from 185 to 783 ng/dl, with a mean of 400 ng/dl and a median of 390 ng/dl. The coefficient of variation was 30%. Postradiation 3-month testosterone levels ranged from 163 ng/dl to 796 ng/dl, with mean and median values of 356 ng/dl and 327 ng/ml, respectively. The coefficient of variation was 34%. The 3-month value was significantly lower than the pretreatment value (Wilcoxon paired p = 0.0001). The mean absolute fall was 94 ng/dl and the mean percentage fall was 9%. Although the fall in testosterone level was statistically significant, the difference was very small quantitatively. In contrast, serum prostate-specific antigen levels fell dramatically by 3 months after radiation. Testicular scattered doses ranged from 1.84 to 2.42 Gy, with a mean of 2.07 Gy for a prostatic tumor dose of 68 Gy. CONCLUSIONS: Although significant, the fall in serum testosterone level after radiation for localized prostate cancer was small and likely of no pathophysiologic consequence. It is unlikely that scattered testicular radiation plays any significant role in the genesis of this change in testosterone level, which most likely occurs as a nonspecific stress response.

Radiotherapy for stage II testicular seminoma.

PURPOSE: To compare the outcome of patients with Stage II seminoma treated with prophylactic mediastinal irradiation, without any supradiaphragmatic irradiation, and with prophylactic left supraclavicular irradiation (PLSCI). METHODS AND MATERIALS: Between 1960 and 1999, 73 men with Stage II seminoma received postorchiectomy radiotherapy. Before 1984, 36 received prophylactic mediastinal irradiation (Series I); between 1984 and 1992, 17 received no supradiaphragmatic irradiation (Series II); and after 1992, 20 received PLSCI (Series III). The outcomes in these series were compared. RESULTS: The abdominal tumor sizes were as follows: Series I, 2 and 5 and 2 and 5 and 2 and 5 and

Treatment of seminoma arising in cryptorchid testes.

We reviewed the clinical characteristics, treatment methods, and outcome of 26 patients presenting with seminoma arising in an undescended testis. The tumor-bearing testis was located in the iliac fossa in 17 patients and in the inguinal canal in nine. The most common presenting symptoms were pain or an enlarging mass. At diagnosis, the tumors tended to be relatively advanced, and 16 of 26 patients (62%) had nodal metastases. In addition to the paraaortic nodes, metastases were frequent to the ipsilateral iliac and inguinal nodes even in the absence of prior inguinal-scrotal surgery. Four patients had documented pelvic peritoneal tumor seeding. All patients received treatment in addition to resection of the primary tumor. Fifteen patients received radiotherapy only, 10 received chemotherapy only, and one received both modalities. At a median follow-up of 9.6 years, only one patient had relapsed. He was initially treated with radiation and after relapse was successfully salvaged with chemotherapy. The 5 and 10-year disease-free rate was 96%, and the 5 and 10-year survival rates were 92% and 79%, respectively. Appropriate treatment of seminoma arising in an undescended testis results in an excellent outcome equivalent to that observed for the more usual scrotal seminomas.

Influence of radiotherapy on node-positive prostate cancer treated with androgen ablation.

PURPOSE: Patients with node-positive prostate cancer that is regionally localized (T1-4, N1-3, M0) have a relatively poor prognosis when a single-treatment modality such as radical surgery, definitive radiotherapy, or androgen ablation is used. While promising results using radical surgery and androgen ablation have been reported, there are no data to support an analogous approach using local radiotherapy and androgen ablation. In this retrospective review, the outcome after local radiotherapy and early androgen ablation (XRT/HORM) was compared to early androgen ablation alone (HORM). METHODS AND MATERIALS: Between 1984 and 1992 there were 181 patients treated with HORM and 27 patients treated with XRT/HORM at the University of Texas M. D. Anderson Cancer Center. The nodal status of all patients was established pathologically by lymph node dissection, which was terminated after frozen section confirmation of involvement. In the majority of cases androgen ablation was by orchiectomy. The median dose to the prostate in XRT/HORM group was 66 Gy. The median follow-up was 45 months; 49 months for the HORM group and 25 months for the XRT/HORM group. RESULTS: The distribution of prognostic factors between the HORM and XRT/HORM groups was similar, with the exception of tumor grade. There was a significantly larger proportion of high grade tumors in the HORM group. In terms of actuarial disease outcome, at 4 years the results of patients in the HORM group were significantly worse, including a rising prostate specific antigen (PSA) of 53%, any disease progression of 32%, a rising PSA or disease progression of 55%, and local progression of 22%. None of the patients in the XRT/HORM group failed biochemically or clinically. To determine the impact of grade on these findings, the analyses were repeated, using only those with grade 2 tumors. A similar pattern was evidenced with significantly worse actuarial outcome at 4 years for the HORM group using the endpoints of a rising PSA (46%), any disease progression (24%), and a rising PSA or disease progression (47%). CONCLUSION: Node-positive prostate cancer patients with regionally localized disease fared significantly better when combined local radiotherapy and early androgen ablation were used, as compared to early androgen ablation alone. Although the number of patients in the XRT/HORM group was small and follow-up was short, the combined treatment had a dramatic effect on disease outcome and, therefore, a larger prospective randomized trial is warranted.

Radiotherapy and androgen ablation for clinically localized high-risk prostate cancer.

PURPOSE: The response of patients with clinical stages T1-4 prostate cancer to radiotherapy is variable. A particularly poor prognostic group has been found to be comprised of those with pretreatment prostate specific antigen (PSA) levels above 30 ng/ml with any tumor grade, or PSA levels > 10 and < or = 30 with tumors grade 3 or 4. These patients have over an 80% actuarial risk of biochemical failure 3 years after definitive external beam radiotherapy. Thus, patients with these high-risk features require more aggressive therapy. During the last 3-4 years, the policy to treat such patients with radiotherapy and androgen ablation (XRT/HORM) was instituted. A retrospective comparison was made between high-risk patients treated with radiotherapy alone (XRT) vs. XRT/HORM. METHODS AND MATERIALS: Between 1987 and 1991, there were 81 high-risk patients treated with XRT. There were 38 high-risk patients treated with XRT/HORM between 1990 and 1992. The median follow-up was 37 months for the XRT group and 22 months for the XRT/HORM group. No patient had clinical, radiographic, or pathologic evidence of lymph node involvement. The median dose to the prostate was 66 Gy for the XRT group and 68 Gy for the XRT/HORM group. RESULTS: The distributions of several potential prognostic factors were analyzed. Significant differences between the groups were observed for tumor grade, pretreatment prostatic acid phosphatase, and age. The XRT/HORM group was composed of patients with worse features, including a greater proportion of patients with grade 4 tumors, more with abnormal acid phosphatase levels, and more under 60 years of age. The actuarial incidence of a rising PSA at 3 years for the XRT group was 81% vs. 15% for the XRT/HORM group (p < 0.0001). In addition, local relapse at 3 years was 34% for the XRT group and 15% for the XRT/HORM group (p < 0.02). There was no difference between the groups in terms of survival. Cox proportional hazards analyses were performed using several disease end points, including a rising PSA, a rising PSA or disease relapse, any disease relapse, and local relapse, and the only prognostic factor of independent predictive value was treatment group, i.e., XRT vs. XRT/HORM. CONCLUSIONS: Based on biochemical and disease relapse end points, definitive radiotherapy is insufficient treatment for high-risk prostate cancer patients. The addition of androgen ablation significantly reduces the recurrence rates, although longer follow-up is needed to determine if the combined treatment impacts significantly on survival.

Radiation therapy in the management of desmoid tumors.

PURPOSE: To evaluate the outcome of patients with extra-mesenteric desmoid tumors treated with radiation therapy, with or without surgery. METHODS AND MATERIALS: The outcome for 75 patients receiving radiation for desmoid tumor with or without complete gross resection between 1965 and 1994 was retrospectively reviewed utilizing univariate and multivariate statistical methods. RESULTS: With a median follow-up of 7.5 years, the overall freedom from relapse was 78% and 75% at 5 and 10 years, respectively. Of the total, 23 patients received radiation for gross disease because it was not resectable. Of these 23 patients, 7 sustained local recurrence, yielding a 31% actuarial relapse rate at 5 years. Radiation dose was the only significant determinant of disease control in this group. A dose of 50 Gy was associated with a 60% relapse rate, whereas higher doses yielded a 23% relapse rate (p < 0.05). The other 52 patients received radiation in conjunction with gross total resection of tumor. The 5- and 10-year relapse rates were 18% and 23%, respectively. No factor correlated significantly with disease outcome. There was no evidence that radiation doses exceeding 50 Gy improved outcome. Positive resection margins were not significantly deleterious in this group of irradiated patients. For all 75 patients, there was no evidence that radiation margins exceeding 5 cm beyond the tumor or surgical field improved local-regional control. Ultimately, 72 of the 75 patients were rendered disease-free, but 3 required extensive surgery (amputation, hemipelvectomy) to achieve this status. Significant radiation complications were seen in 13 patients. Radiation dose correlated with the incidence of complications. Doses of 56 Gy or less produced a 5% 15-year complication rate, compared to a 30% incidence with higher doses (p < 0.05). CONCLUSIONS: Radiation is an effective modality for desmoid tumors, either alone or as an adjuvant to resection. For patients with negative resection margins, postoperative radiation is not recommended. Patients with positive margins should almost always receive 50 Gy of postoperative radiation. Unresectable tumors should be irradiated to a dose of approximately 56 Gy, with a 75% expectation of local control.

Prostate-specific antigen cancer volume: a significant prognostic factor in prostate cancer patients at intermediate risk of failing radiotherapy.

PURPOSE: Although the pretreatment serum prostate-specific antigen level (PSAL) is the single-most significant predictor of local and biochemical control in prostate cancer patients treated with radiotherapy, it is relatively insensitive for patients with a PSAL in the intermediate range (4-20 ng/ml). PSA density (PSAD) has been shown to be slightly more predictive of outcome than PSAL for this intermediate risk group; however, this improvement is small and of little use clinically. PSA cancer volume (PSACV), an estimate of cancer volume based on PSA, has recently been described and has been purported to be more significant than PSAL in predicting early biochemical failure after radiotherapy. We report a detailed comparison between this new prognostic factor, PSAL, and PSAD. METHODS AND MATERIALS: The records of 356 patients treated with definitive external beam radiotherapy for regionally localized (T1-4,Nx,M0) adenocarcinoma of the prostate were reviewed. Each patient had a PSAL, biopsy Gleason score, and pretreatment prostate volume by transrectal ultrasonography. The median PSAL was 9.3 ng/ml and 66% had Gleason scores in the 2-6 range. The median radiation dose was 66.0 Gy and the median follow-up for those living was 27 months. PSACV was calculated using a formula which takes into account PSAL, pretreatment prostate ultrasound volume, and Gleason score. The median PSACV was 1.43 cc. Biochemical failure was defined as increases in two consecutive follow-up PSA levels, one increase by a factor > 1.5, or an absolute increase of > 1 ng/ml. Local failure was defined as a cancer-positive prostate biopsy, obtained for evidence of tumor progression. RESULTS: The distributions of PSACV and PSAL were similar and, when normalized by log transformation, were highly correlated (p < 0.0001, linear regression). There was a statistically significant relationship between PSACV and several potential prognostic factors including PSAL, PSAD, stage, Gleason score, and pretreatment prostatic acid phosphatase (PAP). In univariate analyses, PSACV, PSAL, and PSAD proved to be the most significant predictors of both biochemical and local control. In multivariate analyses using Cox proportional hazards models with PSAL, PSAD, PSACV, and PAP as continuous variables, PSAL, PSACV, and Gleason score were significant in predicting biochemical control. Only PSAL was significantly correlated with local control. However, when these analyses were restricted to patients with intermediate PSALs (4-20 ng/ml), only PSACV was significant for predicting both biochemical and local control. CONCLUSION: PSACV was highly correlated with actuarial local and biochemical control and was superior to both PSAL and PSAD in predicting these outcomes in patients with PSALs between 4 and 20 ng/ml.

Prostate cancer in African-American men: outcome following radiation therapy with or without adjuvant androgen ablation.

PURPOSE: To compare the outcome of irradiated clinically localized prostate cancer in African-American and white patients. METHODS AND MATERIALS: This was a retrospective review of 1,201 men, 116 African-American and 1,085 white, with T1-T3, N0/NX, M0 prostate cancer receiving external radiation between 1987 and 1996. Pretreatment characteristics, treatment parameters, and outcome (relapse or rising prostate-specific antigen [PSA] levels, local recurrence, metastatic relapse, and survival) were compared between the groups using univariate and multivariate statistical methods. RESULTS: There were no significant differences between African-American and white patients in T-stage, Gleason score, prostatic acid phosphatase (PAP) level, and testosterone level. African-Americans had a significantly lower incidence of abnormal digital rectal findings and a proportionally higher incidence of obstructive urinary symptoms at presentation and tended to be somewhat younger. A major difference between the two groups was in the significantly higher PSA levels among African-Americans (median, 14 ng/ml) than among white patients (median, 9.5 ng/ml). This translated into a higher incidence of unfavorable disease according to our criteria (39% vs. 25%) among African-Americans and, thus, to the more frequent use of adjuvant androgen ablation and to somewhat higher radiation doses in these patients. With a median follow-up of 42 months the overall 6-year freedom from relapse for African-Americans was 63% compared to 61% for whites (p = 0.634). We found no significant differences in biochemical relapse rates between any subgroups of African-Americans and whites. Specifically, even patients who did not have androgen ablation, when stratified by PSA levels, had similar outcomes regardless of race. Likewise, local recurrence and metastasis rates were not significantly different between the two groups. CONCLUSIONS: Although African-American patients tend to have higher pretreatment PSA levels than white patients, the outcome for the disease is similar in the two groups when stratified by known pretreatment prognostic factors. Our data provide no evidence for the hypothesis that prostate cancer in African-Americans is intrinsically more virulent than in whites.