- Email: [email protected]
Proton therapy for prostate cancer: The initial Loma Linda University experience
494
J.A. Smith / Urologic Oncology: Seminars and Original Investigations 22 (2004) 493–504
Conclusion: Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.
Commentary The protracted clinical course of many prostate cancers is frequently and mistakenly assumed in the lay press, and much medical literature implies that prostate cancer does not require treatment. Many of the earlier reports from Scandinavia helped contribute to this attitude. Increasingly, though, long-term follow-up of Scandinavian populations as well as others show that a significant number of men who are otherwise destined to live 15 years or more suffer death or morbidity from prostate cancer if it is not successfully treated. doi:10.1016/j.urolonc.2004.08.007 Joseph A. Smith, Jr., M.D. Long-term follow-up of radiotherapy for prostate cancer. Swanson GP, Riggs MW, Earle JD, Department of Radiation Oncology, Cancer Care Northwest, Spokane, WA. Int J Radiat Oncol Biol Phys 2004;59:406 –11 Purpose: To determine the long-term outcome of radiotherapy for prostate cancer. Methods and Materials: A total of 136 consecutive patients with prostate cancer underwent primary radiotherapy. All but 4 patients received 6000 cGy to the prostate. The minimal follow-up was 22.9 years. Results: Of the 136 patients, 93 had Stage B (T2), 9 Stage A (T1), and 34 Stage C (T3). Sixty-nine percent of the patients developed recurrence, and 51% of all patients died of prostate cancer. The recurrences developed at a steady state throughout the length of follow-up. One half the recurrences occurred after 10 years, and recurrence was still observed ⬎20 years after treatment. The survival rate at 5, 10, 15, 20, and 25 years was 81%, 59%, 37%, 16%, and 10%, respectively. The recurrence-free survival rate at 25 years was 17%. The median survival for Grade 3– 4 patients was 6.3 years and for Grade 1–2 patients was 13.0 years. The median survival for those with T1 tumors was 12.9 years; T2 tumors, 12.4 years; and T3 tumors, 9.5 years. Conclusion: Despite favorable early results, with long-term follow-up, patients continued to experience prostate cancer recurrence. Unless they died an intercurrent death, they were highly likely to develop recurrence and die of prostate cancer. The conclusions from treatment studies with ⬍15 years of follow-up should be viewed as preliminary. Commentary Few series of either surgical or radiation treatment for prostate cancer use survival as the endpoint because of the necessity for long-term follow-up. Over one-half of the patients in this study died from carcinoma of the prostate and over half of observed recurrences were more than 10 years after treatment. There was still a risk of recurrence even 20 years after therapy. PSA information likely would have predicted which patients were going to recur but data are not included in the manuscript to assess when the first evidence of biochemical failure was apparent. doi:10.1016/j.urolonc.2004.08.006 Joseph A. Smith, Jr., M.D. Proton therapy for prostate cancer: the initial Loma Linda University experience. Slater JD, Rossi CJ Jr, Yonemoto LT, Bush DA, Jabola BR, Levy RP, Grove RI, Preston W, Slater JM, Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA. Int J Radiat Oncol Biol Phys 2004;59:348 –52 Purpose: We analyzed results of conformal proton radiation therapy for localized prostate cancer, with emphasis on biochemical freedom from relapse. Methods and Materials: Analyses were performed for 1255 patients treated between October 1991 and December 1997. Outcomes were measured on primarily in terms of biochemical relapse and toxicity. Results: The overall biochemical disease-free survival rate was 73%, and was 90% in patients with initial PSA 聿4.0; it was 87% in patients with posttreatment PSA nadirs 聿0.50. Rates dropped with rises in initial and nadir PSA values. Long-term survival outcomes were comparable with those reported for other modalities intended for cure. Conclusions: Conformal proton radiation therapy at the reported dose levels yielded disease-free survival rates comparable with other forms of local therapy, and with minimal morbidity. Dose-escalation strategies are being implemented to further improve long-term results.
Commentary There are currently a limited number of institutions utilizing conformal proton radiation therapy. For certain tumors, such as head and neck lesions, the precision of proton therapy seems to offer decided advantages over standard external beam radiation. It has long been a
J.A. Smith / Urologic Oncology: Seminars and Original Investigations 22 (2004) 493–504
495
question as to whether the same can be said for prostate cancer. Slater and colleagues provide follow-up on a large series of prostate cancer patients treated with proton therapy and essentially conclude that results are equivalent, but not superior, to 3-D conformal external beam radiation. doi:10.1016/j.urolonc.2004.08.009 Joseph A. Smith, Jr., M.D. Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer. Ohori M, Kattan MW, Koh H, Maru N, Slawin KM, Shariat S, Muramoto M, Reuter VE, Wheeler TM, Scardino PT, Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY. J Urol 2004;171:1844 –9 Purpose: We developed a model to predict the side specific probability of extracapsular extension (ECE) in radical prostatectomy (RP) specimens based on the clinical features of the cancer. Materials and Methods: We studied 763 patients with clinical stage T1c-T3 prostate cancer who were diagnosed by systematic needle biopsy and subsequently treated with RP. Candidate predictor variables associated with ECE were clinical T stage, the highest Gleason sum in any core, percent positive cores, percent cancer in the cores from each side and serum prostate specific antigen (PSA). Receiver operating characteristic (ROC) analyses were performed to assess the predictive value of each variable alone and in combination. We constructed and internally validated nomograms to predict the side specific probability of ECE based on logistic regression analysis. Results: Overall 30% of the patients and 17% of 1,526 prostate lobes (left or right) had ECE. The areas under the ROC curves (AUC) of the standard features in predicting side specific probability of ECE were 0.627 for PSA, 0.695 for clinical T stage on each side and 0.727 for Gleason sum on each side. When these features were combined predictive accuracy increased to 0.788. The highest value (0.806) was achieved by adding the percent positive cores and the percent cancer in the biopsy specimen to the standard features. The resulting nomograms were internally validated and had excellent calibration and discrimination accuracy. Conclusions: Standard clinical features of prostate cancer in each lobe-PSA, palpable induration and biopsy Gleason sum-can be used to predict the side specific probability of ECE in RP specimens. The predictive accuracy is increased by adding information from systematic biopsy results. The predictive nomograms are sufficiently accurate for use in clinical practice in decisions such as wide versus close dissection of the cavernous nerves from the prostate. Commentary In properly selected patients, nerve-sparing radical prostatectomy does not increase significantly the risk of positive margins. However, some patients simply are not good candidates for a nerve-sparing procedure because of the likelihood of extracapsular extension in the region of the neurovascular bundle. In devising this nomogram, the authors used the parameters known to be associated with a risk of extracapsular extension such as preoperative PSA, clinical tumor stage, Gleason sum, and number and percent of positive biopsy cores. Although each had independent prognostic value, combining the information increased the accuracy. Experienced clinicians intuitively use this type of information in making decisions but nomograms allow a more evidence-based approach. doi:10.1016/j.urolonc.2004.08.005 Joseph A. Smith, Jr., M.D. Radiotherapy after radical prostatectomy: does transient androgen suppression improve outcomes? King CR, Presti JC Jr, Gill H, Brooks J, Hancock SL, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA. Int J Radiat Oncol Biol Phys 2004;59:341–7 Purpose: The long-term biochemical relapse-free survival and overall survival were compared for patients receiving either radiotherapy (RT) alone or radiotherapy combined with a short-course of total androgen suppression for failure after radical prostatectomy. Methods and Materials: Between 1985 and 2001, a total of 122 patients received RT after radical prostatectomy at our institution. Fifty-three of these patients received a short-course of total androgen suppression (TAS) 2 months before and 2 months concurrent with RT with a nonsteroidal antiandrogen and an luteinizing hormone-releasing hormone (LHRH) agonist (combined therapy group); the remaining 69 patients received RT alone. Treatment failure was defined after postoperative RT as a detectable PSA ⬎0.05 ng/ml. Clinical and treatment variables examined included: presurgical PSA, clinical T stage, pathologic Gleason sum (pGS), seminal vesicle (SV) involvement, lymph node involvement, surgical margins, pre-RT PSA, prostate dose, pelvic irradiation, indication for postoperative RT (salvage or adjuvant), and time interval between surgery and RT. Minimum follow-up after postoperative RT was 1 year and median follow-up was 5.9 years (maximum, 14 years) for patients receiving RT alone, and 3.9 years (maximum, 11 years) for patients receiving RT with TAS (combined therapy group). Kaplan-Meier analysis was performed for PSA failure-free survival (bNED) and for overall survival (OS). Cox proportional hazards multivariable analysis examined the influence all clinical and treatment variables predicting for bNED and OS. Results: The median time to PSA failure after postoperative RT was 1.34 years for the combined therapy group and 0.97 years for the RT alone group (p ⫽ 0.19), with no failures beyond 5 years. At 5 years, the actuarial bNED rates were 57% for the combined therapy group compared with 31% for the RT alone group (p ⫽ 0.0012). Overall survival rates at 5 years were 100% for the combined therapy group compared with 87% for the RT alone group (p ⫽ 0.0008). For pGS 聿7, the 5-year bNED rates were 58% for combined therapy and 38% for RT alone (p ⫽ 0.0155), and for pGS 肁8 the 5-year bNED rates were 65% for combined therapy and 17% for RT alone (p ⫽ 0.075). The 5-year OS rates for pGS 聿7 were 100% for combined therapy and 98% for RT alone group (p ⫽ 0.106), and the 5-year OS for pGS
J.A. Smith / Urologic Oncology: Seminars and Original Investigations 22 (2004) 493–504
Conclusion: Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.
Commentary The protracted clinical course of many prostate cancers is frequently and mistakenly assumed in the lay press, and much medical literature implies that prostate cancer does not require treatment. Many of the earlier reports from Scandinavia helped contribute to this attitude. Increasingly, though, long-term follow-up of Scandinavian populations as well as others show that a significant number of men who are otherwise destined to live 15 years or more suffer death or morbidity from prostate cancer if it is not successfully treated. doi:10.1016/j.urolonc.2004.08.007 Joseph A. Smith, Jr., M.D. Long-term follow-up of radiotherapy for prostate cancer. Swanson GP, Riggs MW, Earle JD, Department of Radiation Oncology, Cancer Care Northwest, Spokane, WA. Int J Radiat Oncol Biol Phys 2004;59:406 –11 Purpose: To determine the long-term outcome of radiotherapy for prostate cancer. Methods and Materials: A total of 136 consecutive patients with prostate cancer underwent primary radiotherapy. All but 4 patients received 6000 cGy to the prostate. The minimal follow-up was 22.9 years. Results: Of the 136 patients, 93 had Stage B (T2), 9 Stage A (T1), and 34 Stage C (T3). Sixty-nine percent of the patients developed recurrence, and 51% of all patients died of prostate cancer. The recurrences developed at a steady state throughout the length of follow-up. One half the recurrences occurred after 10 years, and recurrence was still observed ⬎20 years after treatment. The survival rate at 5, 10, 15, 20, and 25 years was 81%, 59%, 37%, 16%, and 10%, respectively. The recurrence-free survival rate at 25 years was 17%. The median survival for Grade 3– 4 patients was 6.3 years and for Grade 1–2 patients was 13.0 years. The median survival for those with T1 tumors was 12.9 years; T2 tumors, 12.4 years; and T3 tumors, 9.5 years. Conclusion: Despite favorable early results, with long-term follow-up, patients continued to experience prostate cancer recurrence. Unless they died an intercurrent death, they were highly likely to develop recurrence and die of prostate cancer. The conclusions from treatment studies with ⬍15 years of follow-up should be viewed as preliminary. Commentary Few series of either surgical or radiation treatment for prostate cancer use survival as the endpoint because of the necessity for long-term follow-up. Over one-half of the patients in this study died from carcinoma of the prostate and over half of observed recurrences were more than 10 years after treatment. There was still a risk of recurrence even 20 years after therapy. PSA information likely would have predicted which patients were going to recur but data are not included in the manuscript to assess when the first evidence of biochemical failure was apparent. doi:10.1016/j.urolonc.2004.08.006 Joseph A. Smith, Jr., M.D. Proton therapy for prostate cancer: the initial Loma Linda University experience. Slater JD, Rossi CJ Jr, Yonemoto LT, Bush DA, Jabola BR, Levy RP, Grove RI, Preston W, Slater JM, Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA. Int J Radiat Oncol Biol Phys 2004;59:348 –52 Purpose: We analyzed results of conformal proton radiation therapy for localized prostate cancer, with emphasis on biochemical freedom from relapse. Methods and Materials: Analyses were performed for 1255 patients treated between October 1991 and December 1997. Outcomes were measured on primarily in terms of biochemical relapse and toxicity. Results: The overall biochemical disease-free survival rate was 73%, and was 90% in patients with initial PSA 聿4.0; it was 87% in patients with posttreatment PSA nadirs 聿0.50. Rates dropped with rises in initial and nadir PSA values. Long-term survival outcomes were comparable with those reported for other modalities intended for cure. Conclusions: Conformal proton radiation therapy at the reported dose levels yielded disease-free survival rates comparable with other forms of local therapy, and with minimal morbidity. Dose-escalation strategies are being implemented to further improve long-term results.
Commentary There are currently a limited number of institutions utilizing conformal proton radiation therapy. For certain tumors, such as head and neck lesions, the precision of proton therapy seems to offer decided advantages over standard external beam radiation. It has long been a
J.A. Smith / Urologic Oncology: Seminars and Original Investigations 22 (2004) 493–504
495
question as to whether the same can be said for prostate cancer. Slater and colleagues provide follow-up on a large series of prostate cancer patients treated with proton therapy and essentially conclude that results are equivalent, but not superior, to 3-D conformal external beam radiation. doi:10.1016/j.urolonc.2004.08.009 Joseph A. Smith, Jr., M.D. Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer. Ohori M, Kattan MW, Koh H, Maru N, Slawin KM, Shariat S, Muramoto M, Reuter VE, Wheeler TM, Scardino PT, Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY. J Urol 2004;171:1844 –9 Purpose: We developed a model to predict the side specific probability of extracapsular extension (ECE) in radical prostatectomy (RP) specimens based on the clinical features of the cancer. Materials and Methods: We studied 763 patients with clinical stage T1c-T3 prostate cancer who were diagnosed by systematic needle biopsy and subsequently treated with RP. Candidate predictor variables associated with ECE were clinical T stage, the highest Gleason sum in any core, percent positive cores, percent cancer in the cores from each side and serum prostate specific antigen (PSA). Receiver operating characteristic (ROC) analyses were performed to assess the predictive value of each variable alone and in combination. We constructed and internally validated nomograms to predict the side specific probability of ECE based on logistic regression analysis. Results: Overall 30% of the patients and 17% of 1,526 prostate lobes (left or right) had ECE. The areas under the ROC curves (AUC) of the standard features in predicting side specific probability of ECE were 0.627 for PSA, 0.695 for clinical T stage on each side and 0.727 for Gleason sum on each side. When these features were combined predictive accuracy increased to 0.788. The highest value (0.806) was achieved by adding the percent positive cores and the percent cancer in the biopsy specimen to the standard features. The resulting nomograms were internally validated and had excellent calibration and discrimination accuracy. Conclusions: Standard clinical features of prostate cancer in each lobe-PSA, palpable induration and biopsy Gleason sum-can be used to predict the side specific probability of ECE in RP specimens. The predictive accuracy is increased by adding information from systematic biopsy results. The predictive nomograms are sufficiently accurate for use in clinical practice in decisions such as wide versus close dissection of the cavernous nerves from the prostate. Commentary In properly selected patients, nerve-sparing radical prostatectomy does not increase significantly the risk of positive margins. However, some patients simply are not good candidates for a nerve-sparing procedure because of the likelihood of extracapsular extension in the region of the neurovascular bundle. In devising this nomogram, the authors used the parameters known to be associated with a risk of extracapsular extension such as preoperative PSA, clinical tumor stage, Gleason sum, and number and percent of positive biopsy cores. Although each had independent prognostic value, combining the information increased the accuracy. Experienced clinicians intuitively use this type of information in making decisions but nomograms allow a more evidence-based approach. doi:10.1016/j.urolonc.2004.08.005 Joseph A. Smith, Jr., M.D. Radiotherapy after radical prostatectomy: does transient androgen suppression improve outcomes? King CR, Presti JC Jr, Gill H, Brooks J, Hancock SL, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA. Int J Radiat Oncol Biol Phys 2004;59:341–7 Purpose: The long-term biochemical relapse-free survival and overall survival were compared for patients receiving either radiotherapy (RT) alone or radiotherapy combined with a short-course of total androgen suppression for failure after radical prostatectomy. Methods and Materials: Between 1985 and 2001, a total of 122 patients received RT after radical prostatectomy at our institution. Fifty-three of these patients received a short-course of total androgen suppression (TAS) 2 months before and 2 months concurrent with RT with a nonsteroidal antiandrogen and an luteinizing hormone-releasing hormone (LHRH) agonist (combined therapy group); the remaining 69 patients received RT alone. Treatment failure was defined after postoperative RT as a detectable PSA ⬎0.05 ng/ml. Clinical and treatment variables examined included: presurgical PSA, clinical T stage, pathologic Gleason sum (pGS), seminal vesicle (SV) involvement, lymph node involvement, surgical margins, pre-RT PSA, prostate dose, pelvic irradiation, indication for postoperative RT (salvage or adjuvant), and time interval between surgery and RT. Minimum follow-up after postoperative RT was 1 year and median follow-up was 5.9 years (maximum, 14 years) for patients receiving RT alone, and 3.9 years (maximum, 11 years) for patients receiving RT with TAS (combined therapy group). Kaplan-Meier analysis was performed for PSA failure-free survival (bNED) and for overall survival (OS). Cox proportional hazards multivariable analysis examined the influence all clinical and treatment variables predicting for bNED and OS. Results: The median time to PSA failure after postoperative RT was 1.34 years for the combined therapy group and 0.97 years for the RT alone group (p ⫽ 0.19), with no failures beyond 5 years. At 5 years, the actuarial bNED rates were 57% for the combined therapy group compared with 31% for the RT alone group (p ⫽ 0.0012). Overall survival rates at 5 years were 100% for the combined therapy group compared with 87% for the RT alone group (p ⫽ 0.0008). For pGS 聿7, the 5-year bNED rates were 58% for combined therapy and 38% for RT alone (p ⫽ 0.0155), and for pGS 肁8 the 5-year bNED rates were 65% for combined therapy and 17% for RT alone (p ⫽ 0.075). The 5-year OS rates for pGS 聿7 were 100% for combined therapy and 98% for RT alone group (p ⫽ 0.106), and the 5-year OS for pGS