Primary radiation therapy for localized prostate cancer

Urologic Oncology 7 (2002) 239–257

Original article

Primary radiation therapy for localized prostate cancer Tony Y. Eng, M.D.*, Charles R. Thomas, Jr., M.D., Terrence S. Herman, M.D. Department of Radiation Oncology, University of Texas Health Science Center, San Antonio, TX 78284, USA, and the Cancer Therapy and Research Center, 7979 Wurzbach Road, San Antonio, TX 78229, USA Received 10 August, 2001; received in revised form 13 January 2002; accepted 11 May, 2002

Abstract Prostate cancer in men is similar to breast cancer in women; both cancers rank first, respectively, in incidence and are normally responsive to radiation therapy. In addition, advances in mammography help detect earlier breast cancers, and the development and refinement of prostatic specific antigen (PSA) has resulted in early detection of low-stage localized prostate cancers. This has generated debate over the proper management of localized prostate cancer. While there have not been any controlled, prospective, randomized trials of sufficient power to compare the various local therapies, based on the current available data, the three commonly used local modalities, surgery, and external beam radiation therapy and brachytherapy (radioactive seed implant), have similar efficacy controlling the disease up to 10 years in many patients. Technological advances in treatment delivery and planning have improved the treatment of prostate cancer with external-beam radiotherapy using three-dimensional conformal radiotherapy (3DCRT), ultrasound-guided transperineal implant, or intensity-modulated radiotherapy (IMRT), as well as proton or neutron beam based therapies. © 2002 Elsevier Science Inc. All rights reserved. Keywords: PSA; external beam radiation therapy; brachytherapy; three-dimensional conformal radiotherapy; ultrasound-guided transperineal implant; intensity-modulated radiotherapy; prostate cancer

1. Introduction The American Cancer Society estimated the number of new cases of prostate cancer was 198,100 in the United States in 2001 and 31,500 deaths [1]. The annual detection rate of prostate cancer has risen then declined coincident with the increased use of prostate-specific antigen (PSA) to screen for prostate cancer. For example, the estimated incidences were 99,000, 165,000, 334,500, and 179,300 in 1988, 1993, 1997 and 1999 respectively [2–5]. While the rates increased markedly between 1988 and 1992, they declined sharply between 1992 to 1995, and somewhat leveled off from 1995 to 1997 [6]. This trend was thought to be a reflection of extensive use of PSA screening in a previously unscreened population and the subsequent increase in diagnoses at an early stage [7]. However, prostate cancer still remains the most common solid tumor in men, followed by lung and colorectal malignancies, and is second only to lung cancer as a cause of cancer death in men [1].

This article presents a general review of current status of primary radiation therapy for localized prostate cancer in light of the new technological innovations in radiation delivery, which have recently become clinically available. * Corresponding author. Tel.: 1-210-616-5648; fax: 1-210-9495085. E-mail address: [email protected] (T.Y. Eng).

There is no recognized single best treatment for localized prostate cancer, as each patient is unique and different. The current treatment options for localized prostate cancer include surgery, radiation therapy, hormonal manipulation, and observation as well as various combination thereof. Radiation treatment can be accomplished by external-beam or brachytherapy (radioactive seed implant). By far, external-beam radiation therapy has been the standard form of radiation treatment for adenocarcinoma of the prostate in the past 30 to 40 years. Recently, with improved technology and treatment planning systems, increasing number of patients have been treated with 3-D conformal techniques. While the relative proportion of patients treated with radical prostatectomy has increased over the past 10 years, the total number treated with radiation therapy also continues to increase. Potential reasons for the continued use of this modality are multiple but include medically non-surgical candidates, relatively low morbidity, cost, preservation of normal sexual function in some patients, less time lost from work, and patient preference. 2. Discussion 2.1. Staging The current staging system is based on the American Joint Committee on Cancer (AJCC) Staging System [8].

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Primary tumor (T) Tx-Primary tumor cannot be assessed T0-No evidence of primary tumor T1-Clinically inapparent tumor not palpable on digital rectal examination nor visible by radiological imaging. Tumor is confined to the prostate. T1a-tumor incidental histological finding in 5% of resected tissue T1b-tumor incidental histological finding in 5% of resected tissue T1c-tumor identified by needle biopsy (often because of elevated screening PSA) T2-Clinically palpable tumor confined within the prostate. T2a-involves only one lobe T2b-involves both lobes T3-tumor extends through the prostate capsule T3a-extracapsular extension (unilateral or bilateral) T3b-seminal vesicle involvement T4-Tumor fixation or tumor invades adjacent structures T4a-tumor involves bladder neck T4b-tumor involves external sphincter T4c-tumor involves rectum T4d-tumor involves levator muscles T4e-tumor extends to pelvic sidewall 2.2. Regional lymph nodes (N) Nx regional lymph nodes cannot be assessed N0-No regional lymph node metastasis N1-metastasis in regional lymph nodes 2.3. Distant metastasis (M) Mx Distant metastasis cannot be assessed M0-No distant metastasis M1-distant metastasis M1a-Nonregional lymph node(s) M1b-Bone(s) M1c-Other site(s) 2.4. Transrectal ultrasound (TRUS), computed tomography (CT), and magnetic resonance imaging (MRI) staging Although cancer staging by imaging techniques, including TRUS, CT, and MRI, have improved steadily and provided useful information, each has specific limitations by itself and accurate diagnosis and staging of prostate cancer with any single imaging modality are still limited. TRUS is a low-cost simple procedure and remains one of the essential parts of prostate cancer evaluation. CT is less operator-dependent and provides size, density and symmetry information and is relatively cost effective in staging prostate cancer whereas MRI provides better specific detailed architectural information of the prostate gland, its border, in particular the prostatic apex, and adjacent organs. Some of the new emerging modalities, including color and power Doppler ultrasonography, ultrasound contrast agents, intermittent and harmonic ultrasound imaging, MR contrast imaging, MRI with fat suppression,

MRI spectroscopy, three-dimensional MRI spectroscopy imaging (MRSI), elastography, and radioimmunoscintigraphy have been recently reviewed by el-Gabry and associates [9]. Although most of these newer imaging techniques are limited in availability and require further validation, several studies have demonstrated that combining conventional MRI findings with metabolic abnormalities provided by MR spectroscopic imaging (MRSI) can significantly improve cancer localization and assessment of its spread outside the prostate, thus improve diagnosis, staging, and treatment planning for patients with prostate cancer [10–12]. Potentially MRI/MRSI may impact upon clinical outcomes in the future. At present, there is no standard imaging modality that can reliably stage prostate cancer. PSA, digital rectal examination (DRE), TRUS and TRUS-directed sextant biopsies are currently the diagnostic procedures of choice for the clinical staging of patients with potentially organ-confined cancer of the prostate. Abdominal/pelvic CT/MRI may not be necessary in asymptomatic patients with newly diagnosed, untreated prostate cancer patients with low risks of abnormal abdominal/pelvic findings [13,14] while in selected patients, prostatic MRI with an endorectal surface coil may improve tumor localization, and help detect capsular penetration, seminal vesicle invasion, and neurovascular bundle involvement [15]. One study shows the sensitivity and specificity of 66% and 85% for extracapsular extension (ECE), and 75% and 93% for seminal vesicle involvement (SVI), respectively [16]. Table 1 shows the comparison of various imaging techniques in staging prostate cancer [17–24]. As the tumor grade and PSA levels are good indicators of the likelihood of positive pelvic, D’Amico et al. [25] advocate a combined modality staging using the PSA, biopsy Gleason sum, percent positive biopsies, and endorectal coil MRI (erMRI) for clinically localized prostate cancer patients. In their study of 480 surgically managed prostate cancer patients, combined modality staging can predict pathologic stage and postoperative PSA failure in selected patients. Patients with PSA 20 ng/mL, biopsy Gleason sum 8, or erMRI positive for extraprostatic involvement were found to be at high risk (67%) for postoperative PSA failure within 3 years. In the subset of intermediate-risk patients with a positive erMRI for either ECE or SVI and at least 50% positive biopsies, all had extraprostatic disease and failed biochemically by 47 months postoperatively. 2.5. Comparing radiation with surgery It is very difficult to compare outcome between surgery and radiotherapy without well-designed randomized trials. In 1995, the American Urological Association published the results of a five-year effort to develop guidelines for the treatment of localized prostate cancer [26]. The panel searched the MEDLINE database for all articles from 1966 to 1993 on stage T2 (B) prostate cancer, selected, and analyzed outcomes data for radical prostatectomy, radiation therapy and surveillance as treatment alternatives. The panel found the outcomes data in-

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Table 1 The comparison of various imaging techniques in staging prostate cancer

Capsular invasion Accuracy Sensitivity Specificity Seminal vesicle invasion Accuracy Sensitivity Specificity Overall Staging Accuracy Sensitivity Specificity

TRUS (17,18)

ErMRI(16,17– 19)

MRI(20,21)

CT (21–24)

57 23–30 77–86

70 38–71 47–100

70–77 20–55 90–92

65 14 100

87 33–40 100

78 60–100 83–94

94 83 96

50–65 50 77

65–75 60 69

79 60 91

Nodal detection 79–81 14–66 89–90

TRUS-Transrectal Ultrasound; CT-Computed Tomography; MRI-Magnetic Resonance Imaging; ErMRI-Endorectal coil Magnetic Resonance Imaging.

adequate for valid comparisons of treatments. Differences were too great among treatment series with regard to such significant characteristics as age, tumor grade and pelvic lymph node status (staging). One recommendation that reached the level of standard (a practice that should be performed in all patients) is that all patients with clinically localized disease should be offered, as a minimum, radical prostatectomy, radiation therapy, or surveillance as options in the management of their disease. While various differences were found between treatment series with these widely different types of therapy, the drafters of this document found that the dramatic differences in patient selection for each type of treatment precluded an unbiased comparison of treatment efficacy. Some of the selection biases included non-surgical candidates in the radiation group and pathologically staged patients in the prostatectomy group while radical prostatectomy patients also tended to have higher grade and to be younger. In general, most retrospective radiotherapy series tend to include patients who were not operative candidates being referred for definitive radiotherapy. These patients were typically older with more clinically advanced and more aggressive tumors. Most patients were without pathologic lymph node status information and treated with obsolete techniques comparing to modern modes of radiotherapy that can deliver a higher dose of radiation without much increase in morbidity. Fowler et al [27] published a non-randomized study of 357 prostate cancer patients comparing radical prostatectomy with radiation therapy. Although the overall survival rate was higher in the patients treated with surgery, the cause-specific survival was not significantly different between the two groups. A high risk of death from co-morbidity was observed in the radiation therapy group who were not surgical candidates. In a study of 389 patients with clinical stage T1 and T2 prostate adenocarcinoma with pre-treatment PSA levels 10ng/ml, Keyser et al [28] reported similar 5-year PSA disease-free survival rate of 70% in both groups of patients treated with surgery or radiation therapy. To further characterize outcomes of radiation therapy, which could be compared head-to-head with radical prostatectomy, Hanks [29,30] reported an analysis of the 104 patho-

logically staged patients with Tlb-T2N0M0 (clinical stage A2B) prostate cancer who were treated as part of RTOG 7706. These patients, who were similar to surgical candidates (mean age 67, 61% well differentiated, 30% moderately differentiated, 8% poorly differentiated) and who were followed for a median period of 7.6 years, had quite good outcomes. Five and 10-year survivals were 87% and 63% which were comparable to an age-matched control. Local tumor control was achieved at 5 and 10 years in 93% and 84%. At 5 and 10 years, 90% and 79% were free of metastatic disease and the cause specific survival of all patients was 86% at 10 years. These outcome results were similar to some of the published surgical series with comparable long-term outcome [30–32]. Those patients in the RTOG 7706 who were not surgically staged had a statistically significant reduced survival and earlier metastases [33]. Recently, retrospective comparison studies have examined outcomes of patients stratified by several prognostic factors. Kupelian and associates reviewed their experience in the PSA era with external beam radiotherapy (RT) vs. radical prostatectomy (RP) for clinical stage T1-2 prostate cancer [34]. Of the 551 eligible patients reviewed, 253 were treated with RT and 298 with RP. The median pretreatment PSA level for RP patients was 8.1 ng/ml vs. 12.1ng/ml for the RT patients. The median radiation dose was 68.4 Gy. Positive margins were reported in 49% after RP. The median follow-up time was 42 months. By stratifying cases using PSA levels and biopsy Gleason score, treatment outcome is equivalent after either radiotherapy or surgery. The 5-year biochemical relapse– free survival (bRFS) rates for RT vs. RP were 43% vs. 57%, respectively. Multivariate time-to-failure analysis showed pretreatment PSA level and biopsy Gleason scores to be the only independent predictors of relapse. Clinical stage and treatment modality were not independent predictors of failure. The 5-year RFS rates for the low-risk (PSA 10.0 and GS 7) vs. high-risk risk (PSA 10.0 or GS 7) groups were 81% vs. 34%, respectively. There were more low-risk patients treated with RP. Forty-eight percent of RP patients were low-risk cases vs. 33% of RT patients. The rate of surgical margin involvement in RP patients was 39% in the low-risk group vs. 59% in the high-risk group.

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For low-risk patients, there was no difference between radiotherapy and surgery, even when negative margins were achieved. The 5-year RFS rates for patients treated with RT vs. RP were 81% vs. 80%, respectively. The bRFS rates for patients with negative margins were identical to the bRFS rates of patients treated with radiotherapy. For high-risk patients, the 5-year RFS rates for patients treated with RT vs. RP were 26% vs. 37%, respectively. However, patients with positive surgical margins fared significantly worse. The 5-year bRFS was 21% with positive margins, compared to 62% with negative margins. Similarly, in a retrospective study of 1624 patients with prostate cancer, D’Amico and associated found the pretreatment PSA, biopsy Gleason score, and clinical stage (T3,4 vs. T1,T2) were independent predictors of time to post-treatment PSA failure for both surgically and radiation managed patients [35]. With proper stratification of these predictors, there was no statistical difference in the 2-year PSA failurefree survival for patients with a pretreatment prostate specific antigen of 5 to 20 ng/ml managed definitively with either external beam radiation therapy or radical prostatectomy. Overall, retrospective data on long-term survival rates are comparable to those achieved by radical prostatectomy; the overall 15-year survival rates range 40% to 60%, even though some of these patients were non-surgical candidates because of locally advanced disease [36–40]. 2.6. Pre and post-treatment PSA The pre-treatment PSA is the most consistent prognostic variable of outcome after definitive radiation therapy. In general, most study series show that as pre-treatment PSA level and Gleason score increase, the biochemical control rate decreases. Zagars and coworkers from MD Anderson Cancer Center have analyzed the pretreatment PSA levels and the biochemical outcome after conventional external beam radiotherapy in 461 patients with stages T1-T2 disease [41]. The results, as expected were dependent on pre-treatment PSA levels. The 5 year PSA relapse free survival rates for patients with pretreatment PSA levels of 4, 4–10, 10–20, and 20 ng/ml were 91%, 69%, 62%, 38% respectively. In an analysis of a larger group of 938 patients with localized disease who were treated with definitive radiation therapy in the PSA era, the control rates for patients with pre-treatment PSA level of 4, 4–10, 10–20, and 20 ng/ml were 84%, 66%, 49%, 11% respectively [42]. Similarly, Zietman et al. [43] found that patients with a pretreatment PSA level of higher than 15 had a significantly lower relapse free survival. The 4-year relapse free survival rate for patients with pretreatment PSA 15 ng/ml was 6% compared to 65% for patients with PSA 15ng/ml. Data from Cleveland Clinic show a control rate of 100% and 65% in 253 patients with T1-2 disease and pre-treatment PSA level of 4 and 4–10 ng/ml respectively and these control rates were not significantly different from that observed in the surgical group [44]. Schellhammer has demonstrated well that those patients who are without evidence of disease relapse following treatment are likely to

have low levels of PSA [45]. In a group of 78 patients who were without evidence of disease 3 years following therapy, 38.5% of patients had a PSA 0.5 ng/ml, 38.5% had levels between 0.6–4.0 ng/ml, and only 23% had levels 4.0 ng/ml. (Of interest, seven patients had PSA’s greater than 10.0). In a group of 63 patients from the University of Wisconsin who were followed prior to and following radiation with serial PSAs, both initial and nadir PSA effectively predicted the outcome of therapy [46]. Mean pretreatment PSA in patients who were disease free, had local failure, or failed with metastatic disease were 9.6, 34.0, and 56.0 ng/ml, respectively. The nadir PSA’s for these three groups following treatment were 0.9, 2.8, and 9.2 ng/ml, respectively. This, it appears that both pre and post treatment PSA have a strong association with the outcome of treatment with external beam irradiation. Zagars et al. [47] have confirmed this concept in a group of patients from M.D. Anderson Cancer Center (MDACC). In a group of 347 patients with stage A2 (27%), B (33%), and C (40%) disease, and with a mean follow-up of 26 months, the actuarial risk of a rising PSA at 1, 2, 3, 4, and 5 years was 11%, 28%, 34%, 38%, and 38%, respectively. At 4 years of followup, freedom from relapse in patients with a 3-month PSA level 2 ng/ml was 95%. Conversely, in patients with a PSA between 2–10 ng/ml and in those with a PSA 10 ng/ml, the freedom from relapse rate was 50%. Thus, it appears that an optimal target for PSA nadir at 3 months should be less than 2 ng/ml in patients treated with radiation therapy. Consideration may be given in those patients who do not reach such a nadir to begin hormonal therapy. Recently Shipley and associates also published a large multi-institutional pooled analysis of external beam radiation therapy alone for clinically localized prostate cancer involving 1765 patients with T1-2 cancers [48]. The 7-year PSA relapse-free survival rate was 73% for those patients with pretreatment PSA levels 10 ng/ml. More importantly, among those 302 patients who were followed for at least 5 years, only 5% relapsed from the 5th to the 8th year. Most of these patients were treated with advanced equipment and techniques such as 3D conformal radiotherapy. 2.7. PSA nadir after radiation Unlike surgery, post-therapy PSA levels do not always fall to undetectable levels even after successful radiotherapy. The definition of the nadir PSA value after radiation therapy is controversial. By changing the definition of biochemical control, statistically significant differences in treatment outcome could be obtained [49]. Nevertheless, several studies showed that nadir levels of 1.0 ng/ml was a critical independent variable predicting for an improved biochemical outcome [50–52]. Although these investigators did not find further improvement of outcome using a lower cut-off value of 0.5 ng/ml or less, more recent studies have shown that there are significantly less treatment failures among patients with PSA nadir levels of 0.5 ng/ml [53–55]. The 5-year PSA relapse free survival rates were 90–91% and 55–72% for patients with post-radiotherapy nadir levels of 0.5 and

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0.6–1.0 ng/ml respectively. It appears that the most practical definition of PSA failure may in fact be linked to the pretreatment PSA levels [56]. Kavadi et. [50] analyzed the disease outcome in 427 patients with clinical stages T1-4 prostate cancer treated with definitive radiation. The PSA levels continued to fall for up to 12 months after therapy. Thereafter, no further significant declines beyond that were seen. Although the time to nadir was not found to be a significant determinant of outcome, the PSA levels at 3 and 6 months and the nadir level were individually highly correlated with outcome. The post-treatment nadir PSA value was found to be a significant determinant of outcome and was second only to the pretreatment value. Only patients whose nadir falls below 1 ng/ml can be considered to have biochemical complete remission. 2.8. Rising PSA after radiation A transient rise in PSA can occur after radiation treatment, especially after brachytherapy. Recently, Vijayakumar and colleagues have investigated the impact of external beam radiotherapy upon PSA levels during initial follow-up [57]. Analyzing a group of 9 patients who received pelvic radiotherapy but did not have prostate cancer and comparing these men with a group of healthy volunteers, the authors drew weekly PSA levels. In those patients who received pelvic radiotherapy, significant increases in PSA were observed during treatment. The time to peak PSA was 4.2 weeks and thereafter declined. The degree of PSA increase ranged from 50 to 650%. This finding should be considered during initial follow-up of these patients. Nevertheless, the ASTRO consensus has established the definition of biochemical failure as three consecutive rises of PSA value from a nadir level [58]. The definition of nadir PSA level after curative radiotherapy is also controversial. However, in general, most data have shown that the lower the post-treatment PSA nadir levels (1.0 ng/ml), the better the outcomes were [59–61]. In one study, the 5 year PSA relapse free survival rates were 91% and 72% for patients with a post-treatment nadir of 0.5 ng/ml and 0.5–1.0 ng/ml respectively [54]. When the PSA nadir level was 1.0 ng/ml, the 5 year biochemical relapse was 17%, compared to 70% for those with post-therapy nadir of 1.0 ng/ml [59]. The rate of PSA rises after radiotherapy may help distinguish between local and distant failures. Patients with a slowly rising PSA appear to be less likely to have distant metastases and more likely to have a local failure [62]. Some of the variables that help predict distant metastases are PSA recurrence less than 2 years following surgery, tumors with Gleason score (GS) greater than 7, and positive seminal vesicles or positive lymph nodes at the time of surgery [63]. 2.9. Tumor grade (Gleason score) Prostate tumor grade is one of the important prognosticators in treatment outcome. The most commonly used grading system is the Gleason score system, which is based on

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architectural criteria [64]. It has been predictive of the lymphatic metastases and eventual prognosis of the patient. Several authors have demonstrated that initial tumor grade dramatically affects the outcome of external beam irradiation [65,66]. In the series of Dugan et al. [67], using the biopsy status of patients following treatment, patients who initially had a well (Gleason scores 2–4) or moderately differentiated (Gleason scores 4–6) tumor had a 22% risk of disease detectable by subsequent prostate biopsy. Conversely, 64% of patients with initially poor differentiated disease (Gleason scores 8) had positive biopsies during follow-up. In a surgical series of 423 patients with stage T1-2 prostate cancer treated with radical prostatectomy, one of the three factors found to independently predict biochemical relapse was Gleason score (GS) from the surgical specimen (P0.002) [68]. The 5-year biochemical relapse-free survival rates for GS 6 vs. GS 6 were 42% vs. 80%, respectively. 2.10. Biopsy vs. prostatectomy Gleason scores Djavan and associates retrospectively reviewed the records of 415 patients who underwent radical prostatectomy in three Dallas area hospitals to evaluate how accurate the needle biopsy Gleason score is in predicting the final score of the radical prostatectomy specimen [69]. They found 12.7% were “overgraded” and 50.1% “undergraded” by needle biopsy. Similarly, Koksal compared the Gleason score determined by 18-gauge core needle biopsies with both the Gleason score and pathological staging on 134 prostatectomy specimens [70]. The potential for grading error was greatest with welldifferentiated tumors with only 15% of Gleason score 2–4 on needle biopsy correctly graded. Of the patients with Gleason score 5–7 on needle biopsy, 97% were graded correctly while all of the Gleason score 8–10 on needle biopsy were graded correctly. Twenty-five percent of patients with a biopsy Gleason score 7 had the cancer upgraded to 7 and interestingly; only 11% of these had tumor confined to the prostate. Thus, some of the patients undergoing radiation (or conservative management) with well-differentiated or moderately differentiated cancers on needle biopsy may in fact have poorly differentiated cancers. Such a high number of Gleason scores made on needle biopsy specimen are “upgraded” and will favor radical prostatectomy in a direct comparison of treatment efficacy. 2.11. Importance of local control It has been long established that, in spite of treatment either with radiation or radical prostatectomy, prostate cancer sometimes recurs. Although radiation therapy will seldom render a patient with an undetectable PSA (and therefore, some level of PSA is not necessarily an adverse predictor), clinical local control is the immediate goal in the treatment of localized prostate cancer. If local control of the tumor is not established, the patient faces a high risk of subsequent disease relapse and development of metastatic disease. This has been confirmed by Zagars et al. [71]. In a group of 601 patients

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with stages A2-C disease (T1b-T3), local recurrence (clinically determined by digital rectal examination with or without biopsy confirmation) developed in 15% of the patients. The actuarial risk of metastatic disease in these patients was 70% at 13 years of follow-up while only 40% at the same period of follow-up in the 508 patients who had achieved local control. In an analysis of 946 patients with prostate cancer treated with external beam radiation, Kaplan and associates also found an overall improvement in disease-specific survival (DFS) in patients who achieved clinical local control irrespective of the T stage [72]. The actuarial 10-year DFS rates in patients with clinical local recurrence (defined as an enlarging nodule or area of induration determined by digital rectal examination) were 52.4%, 54.3% and 34.5% for T1, T2, and T3 disease respectively. The corresponding rates in patients without local recurrence were 84.2%, 71.6% and 55.8% (P0.01). In addition, the investigators found the trend of PSA was more important than biopsy results in predicting which patients would have clinical relapse. At Memorial Sloan-Kettering Cancer Center, the effect of local control on the incidence of distant metastases was evaluated in 679 patients treated with retropubic I-125 implantation [73]. The relative risk of metastatic spread was 4-fold increased in those without local control (defined as having bladder outlet obstruction requiring transurethral resection, tumor progression on digital rectal examination, or positive biopsy at 1 year post treatment) compared to those with local control. The 15-year actuarial distant metastases free survival in those patients with local control was 77% comurthermore, distant metastases in patients with local control were detected earlier than in patients with local relapse suggesting micrometastases present before treatment. Thus, patients with local control experienced a significantly lower incidence of metastases and a better disease-specific survival than patients who failed locally. These data suggest that the existence and re-growth of local residual disease in localized prostatic carcinoma may promote or enhance the spread of metastatic disease. This is consistent with the hypothesis that the enhanced mitotic activity associated with the regrowth process of locally recurring primary tumors initiates the multi-step transformation of non-metastatic tumor cells into metastatic clonogens, leading to increased overall rates of metastasis. Therefore, local control of the primary tumor is required if a long-term cure is to be obtained. 2.12. Conventional external beam radiation Conventional external beam radiation therapy (EBRT) involves immobilization, simulation, treatment planning, and sometimes verification before actual treatment. During a conventional simulation the patient lays down in a supine (or prone to push the small bowels upward out of the pelvic fields) position that is reproducible. Sometimes, custom immobilization is required, especially if a small field is planned. Contrast media for urethra (retrograde urethrogram) bladder and rectum may be required to localize the prostate radio-

graphically. Typically, a “4-field box” technique with two opposing lateral and two anterior-posterior fields is used. Figure 1 shows the typical field orientation treating the prostate cancer with whole pelvic irradiation. Other techniques to treat the prostate include four oblique opposing fields or bilateral arcs to avoid doses to the bladder and rectum. Various modifications of treatment simulation and planning are not uncommon. Most conventional techniques rely on a single-plane dose distribution at the isocenter as opposed to the 3 dimensional dose distribution with modern computerized tomography-based, 3-dimensional conformal radiotherapy (CT-based 3D-CRT) techniques. As the dose of radiation is limited by surround normal tissue, initial observations form the patterns of care studies (1973 to 1975). This suggests that optimal control is obtained with a radiation dose of about 6000 centigray (cGy) for T-0 and T-1 tumors; 6000–6500 cGy for T-2 tumors; 6500–7000 cGy for T-3 tumors; and that 7000 cGy is required only for T-4 tumors [74]. However, with the emergence of higher energy linear accelerators and treatment simulation and planning equipment, a dose range of 6500–7000 cGy is deemed appropriate and no further significant therapeutic advantage beyond 7000 cGy for T3 disease is gained [38]. 2.13. Conventional external beam radiation results Roach and associates recently analyzed the long-term survival of those patients who were treated with curative intent with conventional external beam radiotherapy alone from four prospective phase III randomized trials conducted by the Radiation Therapy Oncology Group between 1975 and 1992 [75]. Most of the patients had tumors clinically staged as T3 (59%), and 36% of the patients with clinically staged T1-2 tumors had pathologically positive lymph nodes. The 10-year disease specific survival for patients with a Gleason score of 2–5, 6–7 and 8–10 was 87, 75 and 44%, respectively, following radiotherapy. Zietman et al. [76] reported long-term results on 1044 patients from a single institution. The biochemical without evidence of disease (bNED) rates were 60% and 40% at 5 and 10 years, respectively, for 504 patients with T1-2 disease who were treated with conventional external radiation therapy. For the remaining 540 patients with T3-4 disease, the 5 and 10 years bNED rates were 32% and 10%. Crook et al. [77] reported an interesting analysis of 226 consecutive patients who had undergone prostate biopsy beginning 12 months after definitive radiation and then every 6 months until negative or until clinical failure. With a mean follow-up of 33 months, the following results were found and are illustrated in Table 2. Out of the original 47 patients with positive biopsies, 39 eventually converted to negative biopsies at a median time of 26 months. The authors explained their findings that radiation injured malignant-appearing cells are in fact non-viable with no supporting evidence for clinically or biologically active disease; continued resolution of pathology over time may occur. The rate of positive biopsies has also been shown by other investigators to decrease with

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Fig. 1. Four-field box technique to cover the prostate and the pelvic nodes. (A) Surface view of the pelvic “4-field box technique” with corner blocks (green); (B) Anterior-posterior digitally reconstructed radiograph (DRR) simulation film (prostate-green, bladder-dark yellow, rectum orange, isocenter-light yellow); (C) Axial view of the four beams (anterior-dark yellow, posterior-blue, right-green, left-orange); (D) Sagittal view of the pelvis with anterior and posterior beams shown.

time after irradiation and the interpretation of early biopsies is often misleading [78]. As the timing and interpretation of post-irradiation prostate needle biopsies are controversial and challenging for the pathologist because of substantial radiationinduced changes in benign and malignant prostatic tissue [79], the American Society of Therapeutic Radiology and Oncology (ASTRO) challenged a multidisciplinary consensus panel to address consensus on specific issues in evidence-based guidelines for prostate re-biopsy after radiation in the management of patients with localized prostatic cancer [80]. The panel sought criteria that would be valid for patients in standard clinical practice as well as for patients enrolled in clinical trials. The panel judged that prostate re-biopsy is not necessary as standard follow-up care and that the absence of a ris-

Table 2 Biopsy results after definitive radiation therapy [72] No evidence of disease Biopsy failure PSA failure Local failure Local and distance failure Metastatic disease

54% 21% 3% 10% 4% 8%

ing PSA level after radiation therapy is the most rigorous end point of total tumor eradication. Subsequently, biochemical failure is often used as the endpoint in most clinical studies. 2.14. Three dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT) The continuing advances in computer hardware and software and radiotherapy equipment have facilitated the implementation of sophisticated 3-D conformal treatment techniques allowing precise delivery of higher doses of external beam radiation to the prostate with steep drop-off of the dose to adjacent organs. Thus the incidence of treatment related side effects are lower with 3-D conformal techniques than with conventional techniques for the same given therapeutic doses of radiation to the tumor [81]. The common techniques of 3D-CRT may involve the use of multiple static fields, custom blocks, sophisticated patient immobilization devices, and CT-based simulation and 3D-treatment planning systems with beam’s eye view [81–85]. The use of beam’s eye viewing of volumes defined on a treatment planning CT scan allows individual selection of beam directions, field sizes and shapes to conform to the shape of the target and minimize radiation dose to surrounding critical normal structures.

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Fig. 3. Prostate dose-volume; (A) Spatial relationship between prostate (pink), bladder (purple), rectum (green), and penile bulb (dark yellow); (B) Volume histogram (x-axis-dose, y-axis-volume) showing 100% volume of the prostate receiving the prescribed dose while much less volume of adjacent organs receiving the same dose.

Fig. 2. Intensity-modulated radiotherapy technique for prostate cancer showing the high-dose isodose lines conforming to the shape of the prostate (pink) while sparing the rectum (green) and the bladder (purple); (A) Axial view; (B) Sagittal view; (C) Coronal view.

To overcome some of the limitations of 3D-CRT, the more complex conformal therapy uses modulated beam intensity in addition to beam shaping to achieve desired dose distribution. This intensity modulated radiation therapy (IMRT) technique involves the use of non-uniform dynamic radiation beams of various intensities to achieve conformal dose distributions (Fig. 2). The dose conformity observed with IMRT is substantially improved with better sparing of critical uninvolved surrounding structures compared with that observed with the 3D-CRT technique. IMRT may potentially be superior to 3DCRT in allowing dose escalation without increased morbidity. One of the commercially available systems, the Peacock system, uses a special multileaf collimator (MIMiC) and dynamic arc therapy with segmented fields, similar to a moving

strip to deliver the dose distribution. Unlike conventional treatment planning process (forward planning) where the orientation and number of beams are chosen to get the desired dose distribution, IMRT uses inverse planning process or optimization that allows the desired dose distribution to be chosen first followed by the determination of orientation, number and intensity of beams that are required to achieve that dose distribution [86]. It can yield dose distributions that conform closely to the three-dimensional shape of the target volume while selectively minimizing dose to normal structures by allowing the beam intensity to vary across those shaped fields. Thus, IMRT offers the most conformity in the delivery of the desired tumoricidal doses of radiation to the prostate while the doses to various adjacent critical organs can be limited to decrease radiation related morbidity [87–89]. This can be illustrated by a dose-volume histogram (DVH), which shows the radiation dose received by an organ in relation with its volume (Fig. 3). The entire volume of the prostate receives 100% of the prescribed dose (78 Gy), whereas, only about 10% of the bladder and rectum receive the same dose.

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Therefore, unlike the conventional technique with which an increase of complications has been shown with the dose of radiation 70 Gy [38,90], the GI and GU morbidity in patients treated with 3D-CRT is not significantly increased or worsened despite the higher doses, to a certain degree, of radiation used [91–93]. 2.15. Dose escalation and results The reduction in critical pelvic organ irradiation seen with 3D-CRT and IMRT minimizes the treatment related acute side effects and allow modest dose escalation improving the local control rate without increasing late complications. Leibel et al [94] conducted a prospective randomized dose-escalation study on patients treated with conformal 3D-CRT at Memorial Sloan-Kettering Cancer Center. Patients were treated with increasing doses from 64.8–66.6 GY in 87 patients, 70.2 Gy in 138 patients, 75.6 Gy in 69 patients, and 81 Gy in 30 patients. During follow-up, only 1 patient had grade 3 toxicity and the majority of patients experienced either no or only grade 1 toxicity. While pre-treatment PSA levels ranged from 5.4, 21.5, and 30.3 in Tlc-T2b, T2c, and T3 patients, nadir PSA following treatment was 1.4, 1.4, and 1.1 ng/ml, respectively. At three years of follow-up, patients with Tlc, T2a, T2b, T2c, and T3 disease had achieved 97%, 86%, 60%, and 43% rates of PSA-relapse-free survivals [95]. The more recent long term results of 3-D conformal radiotherapy show increased rates of biochemical control and the patients that appear to benefit the most were those with pre-treatment PSA levels 10–20 ng/ml. At Memorial Sloan-Kettering Cancer Center, the difference in biochemical control was an almost 30% advantage at 5 years with 3-D conformal radiotherapy [96]. Hanks et al. [97] reported the 5-year results on 232 prostate cancer patients who were treated with 3D-CRT. The 5-year-bNED rate was 75% for those patients with pre-treatment PSA of 10–20 ng/ml and were treated to 76 Gy compared to 35% for those treated to only 70Gy. For patients with a pretreatment PSA level of 20 ng/ml, the bNED rates were 32% and 10% respectively. The University of Texas M.D. Anderson Cancer Center reported the preliminary results of a phase III randomized radiotherapy dose-escalation study comparing 70 Gy (4-field box technique) with 78 Gy (six-field conformal technique) for T1-T3 prostate cancer [98]. Of the 301 assessable patients, a substantial improvement in freedom from biochemical failure rates for those with a pretreatment PSA of 10 ng/ml was seen. At a median follow up of 40 months, the freedom from biochemical failure rates for the 70-Gy and 78-Gy groups were 48% and 75% respectively. Zelefsky et al. [99] reported the results of 743 patients who were treated with 3D-CRT at Memorial Sloan Kettering Cancer Center. In this study, the tumor target dose was increased from 64.8 to 81 Gy in increments of 5.4 Gy. Of patients receiving 75.6 Gy, 90% achieved a PSA nadir of 1.0 ng, whereas for those treated with 70.2 Gy and 64.8 Gy, only 76% and 56% achieved that nadir respectively. A positive biopsy at 2.5 years after 3D-CRT was observed in

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only 7% of patients receiving 81.0 Gy, compared with 48% after 75.6 Gy, 45% after 70.2 Gy, and 57% after 64.8 Gy. The 5-year actuarial PSA relapse-free survival for patients with favorable prognostic features (T1-2, pretreatment PSA 10, Gleason 6) was 85%, compared to 65% for those with intermediate (T2c-3 or PSA 10 or Gleason 6) and 35% for the group with unfavorable prognosis (2 poor prognostic features). PSA relapse-free survival was significantly improved in patients with intermediate and unfavorable prognosis receiving 75.6 Gy. An update of this study with 1100 patients with median follow-up of 52 months showed PSA relapse free survival rates for the favorable, intermediate and unfavorable risk patients were 85%, 59% and 39% respectively [100]. Again, the patients who were treated to higher doses ( 75.6 Gy) had more favorable PSA relapse free survival in all risk groups (Table 3). Furthermore, high risk patients appeared to benefit from doses 81 Gy with a 5Y RFS of 69% compared to 43% and 24% for those who received 75.6 Gy and 70.2 Gy respectively. Roach et al. [101,102] also observed the bNED advantage of using higher doses of radiation in patients with high-risk features (Gleason score 8-10, T3-4 disease). Other investigators have also shown a direct relationship between dose and PSA relapse free survival in patients treated with 3D-CRT [103–106]. A recent large study of 1041 patients treated at the Cleveland clinic showed a 5year PSA RFS of 81% for those who were treated to 72 Gy compared to 51% for those treated to lower doses [105]. These data provide evidence for a significant effect of dose escalation on the response of prostate cancer to irradiation and that patients with poor prognostic features require more aggressive therapy. Some investigators have noted that treatment to higher doses of radiation, even with 3D-CRT techniques, was associated with an increased incidence of late bladder and rectal toxicity. Zelefsky et al [107] reported 5-year actuarial rates of 15% and 15% of grade 2 late GI and GU toxicity for those patients treated to 75.6 Gy compared to 7% and 8% respectively for those treated to lower doses. Hanks et al. [97] found a 8% 5-year incidence of grade 3/4 rectal toxicity at doses of 75–76 Gy, compared to 2% when the anterior rectal wall dose was shielded to keep the dose at 72Gy. Innovative IMRT is basically a refined form of 3D-CRT and has proven to be more precisely conformal and significantly reduced the incidence of late rectal toxicity [108]. In a study of 232 patients with clinical stage T1c- T3 prostate cancer treated with either 3-D CRT or IMRT to a prescribed dose of 81 Gy, the 2-year actuarial risk of RTOG grade 2 rectal bleeding was 2% for IMRT and 10% for conventional 3D-CRT. Table 3 Five-year PSA relapse free survival rates for different doses of radiation (95) Risk Groups

75.6 Gy

76.5 Gy

P value

Favorable Intermediate Unfavorable

80% 47% 27%

91% 70% 47%

0.03 0.004 0.04

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However, this study showed no significant clinical improvement in acute and late urinary toxicity with IMRT approach. There are preliminary data that suggest IMRT with the addition of BAT (B-mode Acquisition and Treatment). Ultrasoundbased treatment planning may decrease the time to achieving a PSA nadir (Martin Fuss, personal communication, July 2002). Currently, IMRT is little costly and time-consuming. It is not widely available because only a limited number of institutions in the US have that technological capability. 2.16. Particle beam therapy The two more commonly investigated particle beams in the treatment of prostate cancer are protons and neutrons. Both of these particle beams have an identical mass but fast neutrons have a higher relative biological effect (RBE) and linear energy transfer (LET) whereas protons have a unique depth-dose distribution, that is, the proton deposit its energy at the end of its linear track known as “Bragg peak.” By controlling the depth and width of this peak, the majority of the high-dose region can be confined and conformed to the tumor volume while limiting the dose to surrounding normal tissue. Fast neutrons on the other hand have a depth-dose distribution similar to that of conventional photons (X-rays). Because of its high RBE and LET and less dependent on oxygen, neutron therapy was thought to be more effective for eradicating hypoxic cells that are frequently seen in many human tumors. Clinically, neutrons appear to be more effective in controlling slow proliferating tumors like prostate carcinoma. A prospective randomized trial, conducted at Massachusetts General Hospital, of 202 patients with T3-4, N0-2, M0 prostate cancer receiving either EBRT or mixed EBRT and proton therapy showed a significant improvement in local control (84% vs. 19%) in patients with high-grade tumors [109]. There was no improvement in survival. Loma Linda University medical center also reported a study of 643 patients, of these, 106 patients with locally advanced prostate cancer who were treated with proton with or without photon therapy [110,111]. Depending on the pre-treatment PSA, the 4.5-year disease-free survival rate (biochemical control rate) was 100% for patients with an initial PSA of 4.0 ng/ml, and 89%, 72%, and 53% for patients with initial PSA levels of 4.1–10.0, 10.1–20.0, and 20.0, respectively. A more recent study of 319 patients with T1-T2b prostate cancer and initial prostate specific antigen (PSA) levels 15.0 ng/ml or less showed that the overall 5-year clinical and biochemical disease-free survival rates were 97% and 88%, respectively [112]. Initial PSA level, stage, and post-treatment PSA nadir were independent prognostic variables for biochemical disease-free survival. A PSA nadir 0.5 ng/ml or less was associated with a 5-year biochemical disease-free survival rate of 98%, vs. 88% and 42% for nadirs 0.51 to 1.0 and greater than 1.0 ng/ml, respectively. No severe treatment-related morbidity was seen. It appears that patients treated with conformal protons have 5-year biochemical disease-free survival rates comparable to those who undergo radical prostatectomy, and display no significant toxicity.

In the RTOG 77-04 multi-institutional randomized trial where 91 analyzable patients with T3-4, N0-1, M0 disease were randomized to either EBRT or EBRT plus neutron beam, the 10 year local control (58% vs. 70%) and overall survival rates (29% vs. 46%) favor the patients who were treated with mixed neutron beam [113]. A subsequent trial by the Neutron Therapy Collaborative Working Group (NTCWG 85-23) reported the results of 178 patients with locally advanced prostate cancer who were randomized to receive either EBRT or neutron alone [114,115]. The local control rates were 53% and 79% respectively (P0.0007) with no difference in survival. Both randomized trials demonstrate significant improvement in locoregional control with neutron irradiation compared to conventional photon irradiation in the treatment of locally advanced prostate carcinoma. To date, only the mixed beam trial has shown a significant survival benefit. Although particle beam treatment does improve local control, the toxicity and complication rates are also increased when more than 40% of the anterior rectum receiving more than 75 CGE (Cobalt-Gy-equivalent) [116]) or prostate and seminal vesicles treated with a higher dose of Neutron (15 Neutron Gy) in addition to photon [117]. The late and severe complications were more frequently seen in patients who were treated with neutron therapy. The treatment machines currently are expensive and require high maintenance. This technology is still in progress and will take a long time before wide spread application in the US. 2.17. Brachytherapy Brachytherapy involves the precise, ultrasound-guided, placement of radioactive sources (or seeds) into the prostate to deliver a highly concentrated tumoricidal dose of radiation to the prostate while sparing the surrounding organs (rectum and bladder), thus it is the most conformal radiotherapy achievable. It was used in prostate cancer for many decades before teletherapy (external beam therapy). Because of poor and variable techniques and inappropriate patient selection leading to poor results, it was gradually “abandoned” when surgery and EBRT became the preferred treatments. A recent assessment of long-term results of retropubic permanent I-125 implantation of the prostate in 1078 patients with clinically localized prostate cancer treated between 1970 and 1987 at Memorial Sloan-Kettering Cancer Center revealed a greater than expected incidence of local relapse at 15 years [118]. The local recurrence-free survival rates for patients with negative nodes at 5, 10 and 15 years were 69, 44 and 24%, respectively. The inferior outcome was thought to be attributed to technical limitations of the retropubic technique resulting in suboptimal distribution of the isotopes within the prostate. However, this and others’ earlier experiences have served as a framework for the modern transperineal brachytherapy. With continued advent of technology and better understanding of prognostic factors and prostate cancer treatment, during the past 10 years, prostate brachytherapy has resurfaced and continued to gain popularity. One of the main appealing

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reasons is the convenience of this treatment as an outpatient procedure. It is a short procedure with less acute morbidity, better preservation of potency, and fast recovery requiring spinal anesthesia in most cases. Yet, it is a curative and less disruptive therapy without any lifestyle changes post treatment. Patients who are good candidates for brachytherapy must have only localized disease amenable for implant procedure. These patients typically have pre-treatment PSA 10 ng/ml, Gleason score 7, prostate volume 60 cc and T1-2a disease to ensure the risk of extra prostatic spread is very low as no periprostatic tissue is treated adequately. For those patients who may be candidates but are at a higher risk of extra-prostatic involvement (Gleason 7, PSA 10) or large volume, combined with EBRT or androgen ablation may be considered [119,120]. The most common seeds used today are radioactive Iodine125 (I-125) and Palladium-103 (Pd-103). Shielding is not required because of their low energies (21-28 KeV). These seeds are different in their half-life (t1/2) and thus the dose rate; t1/2 for I-125 and Pd-103 are 60 and 17 days and their initial dose rates are approximately 8–10 and 20–24 cGy/hr respectively. Therefore, Pd-103 seeds give off most of the radiation dose faster in about 2–3 months vs. 9–10 months with I123 seeds. Clinically, the tumoricidal effects of both isotopes appear to be similar, although PSA response following brachytherapy with low-dose-rate isotopes is protracted. After a transrectal ultrasound prostate volume study is done, the number of seeds, seed strength, number of needles and their placement within the prostate gland are carefully determined with the aid of a special computer treatment planning system to create a pre-plan. Prostate brachytherapy is typically a relatively short outpatient procedure, done under spinal or general anesthesia. It is a single procedure that often requires no hospitalization afterwards. On the day of the implant, the patient is positioned to match the original prostate volume study. The prostate is implanted according to the pre-plan. Using a special guiding template, hollow needles are inserted into the prostate perineally under ultrasound and sometimes fluoroscopy guidance. The radioactive seeds are injected into the prostate through these needles as they are being withdrawn so that the seeds are distributed properly through out the prostate according to the pre-plan. The procedure usually takes from one to two hours depending on the setup and complexity of the pre-plan. Occasionally, intraoperative modification of the plan may require the injection of a few additional seeds to the “cold spots.” CT scan assesses the final implant quality one month post-operatively. Some of the potential disadvantages of pre-plan method include a change in the prostate volume between the time of the pre-plan and the implant procedure and the difficulty in duplicating the prostate volume to match the original volume in the operating room. A few institutions in the United States have overcome these disadvantages and developed, in an early phase, an on-line, real-time intraoperative dosimetry to allow for fine adjustment in seed placement to obtain opti-

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mal dose distribution [121–123]. The number of radioactive seeds needed is estimated from the prostate volume obtained from a CT scan or TRUS. The treatment plan is created in real-time in the OR just before the implant procedure. Therefore, any changes in prostate size or shape can be accounted for; pubic arch interference can also be avoided. However, real-time intraoperative dosimetry will require additional OR time and the physics/dosimetry team has to expedite the planning process because of time constrain. The use of real-time dosimetry technique does not replace the need for post-implant dosimetric analysis that is recommended by the American Brachytherapy Society [124]. 2.18. PSA levels after brachytherapy Although most patients’ follow up PSA levels drop to 1.0 ng/ml or less, about 35% of the patients experience a temporary benign PSA rise between one and two years (median 18 months) after implantation [125]. These late PSA rises appear to correspond to late recurrence of radiation related urinary symptoms but have no prognostic significance relative to recurrence. The clinical significance of these benign PSA rises is unknown, as most patients will eventually have normal PSA levels. Therefore, such benign PSA rises during the first two years after implant do not suggest poor prognosis and a minimum of 2.5 years follow up to assess PSA response is needed before considering salvage procedures. 2.19. Brachytherapy results Some of the long-term results have been recently reported by Blasko et al. [126–128]. The 9-year results on 230 patients with T1-T2 prostate cancer who were treated with Pd-103 seed implantation were very encouraging. In this study, approximately 40% of the patients had a Gleason score of 6 and 24% had PSA levels of 20. The overall biochemical control rate achieved at 9 years was 83.5%. They observed only 3% and 6% local and distant failure rates respectively. Significant risk factors contributing to failure were serum PSA greater than 10 ng/ml and Gleason sum of 7 or greater. Grimm et al. [128] reported the ten-year biochemical outcomes for 125 patients with early prostate cancer treated with I-125 brachytherapy. They defined biochemical progression as two consecutive rises in serum PSA following treatment. The overall PSA progression free survival rate was 87% at 10 years for low risk patients (T1-T2b disease, PSA 10 ng/ml, and Gleason score 7). For those with a pretreatment PSA of 20 ng/ ml or more, the overall PSA progression free survival rate was 46%. These results are similar to that with Pd-103 isotope above. Ragde et al. [129] recently reported their long-term (12year) results on prostate brachytherapy. There were 229 patients with T1-3 disease who underwent prostate I-125 or Pd103 seed implant procedure. The low risk group of 147 patients underwent implant alone and the high-risk group of 82 patients underwent implant and EBRT. The observed disease free survival (DFS) at 12 years was 66% and 79% respectively, or 70% for both groups combined. The lower DFS in the low

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risk group was attributed to underestimation of Gleason grade as many of the failed patients proved to have distant failure. Some of the reported morbidities of brachytherapy include urinary retention (5%), typically in patients with pre-existing urinary obstructive symptoms, impotence (30%) commonly in elderly patients, and urinary incontinence (24%) for those who had a prior TURP. Prostate brachytherapy achieves a high rate of biochemical and clinical control in patients with clinically organ-confined disease. In comparing brachytherapy (Pd-103) with radical prostatectomy, or external beam radiation therapy, D’Amico and associates conducted a retrospective study of 1872 patients treated between 1989 and 1997 [130]. There were 218, 888, and 766 patients treated with brachytherapy, radical prostatectomy, and external beam radiation therapy respectively. For low-risk patients (T1c-T2a, PSA 10, Gleason 7), the 5-year biochemical outcomes were not statistically different among the three treatment modalities. Stokes reported the biochemical disease-free survival for patients with low or intermediate risk at 5 years is approximately 70% with no significant difference between those patients treated with radical prostatectomy, external beam, or I-125 [131]. Those patients with low T stages and tumor burden and low pre-treatment PSA have done well with prostatectomy, external beam radiation therapy or brachytherapy with approximately 70% to 80% cure rates at 10 or more years [127–129,132,133]. Likewise, those patients with high T stages, high tumor burden, and high pre-treatment PSA have high risk of biochemical failure regardless of treatment modality. Some of the recent long-term results of prostate brachytherapy treated with modern methods in the PSA era are summarized in Table 4 [134–142]. These are retrospective, singleinstitution experience. The patient selection criteria and implant techniques were at the discretion of the investigators with various brachytherapy experiences. The definitions of PSA nadir and disease-free survival used were not uniform. The overall 10-year disease-free survival is approximately 80% in selected patients. Patients treated with external beam radiation therapy plus brachytherapy often had higher mean pretreatment PSA levels, Gleason scores and T stage disease. Currently, there are no prospective randomized multi-institutional data on the combination of brachytherapy with external beam radiation therapy for prostate cancer. 2.20. Hormonal down sizing The exact mechanism of interaction between radiation and hormonal therapy is not clear. It is thought that the reduction of the tumor burden (down sizing) by endocrine therapy may increase the likelihood of total destruction of the remaining cancer cells by irradiation. Zietman et al. [143] have shown that a lower dose of radiation was required to kill the tumor after maximum volume reduction by androgen deprivation. Perhaps, hormonal ablation may induce apoptosis, cell synchronization by shifting of cells in the cell cycle, and reduction of the number of cell clonogens resulting in additive or supraadditive killing effect as postulated by some investigators

[144,145]. Furthermore, as the prostate volume is reduced, it may decrease radiation toxicity to adjacent normal tissues because smaller treatment field is used, as the complication rate is directly related to the organ volume receiving a high dose of radiation. The group of investigators at MSKCC has demonstrated that one salutary effect of neoadjuvant hormonal therapy is the reduction in target volume of the prostate [146]. In a study of 22 patients who received such therapy, the median percentage reduction of target volume after hormonal therapy was 25%. This correlated nicely with a 25% reduction in the rectal volume receiving a high dose of radiation. The median reduction in the volume of the bladder and rectum receiving 95% of the prescribed tumor dose was 46% and 18% respectively [147]. Other investigators also observed a significant volume reduction of prostate of 37% in average after three months of hormonal therapy prior to treatment [148]. The reduction of rectum and bladder volumes receiving 64 Gy of radiation was 20% and 34% respectively. Although combined radiation therapy with hormonal therapy has resulted in significant improvement in the overall progression-free survival when compared with radiation alone in patients with locally advanced disease [149–158], with the exception of the patients with large prostatic volume, routine administration of androgen ablation in combination with radiotherapy for those with early stage disease should be avoided as such therapy can induce significant side effects and complications to include hot flashes, loss of libido, impotence, decrease in muscle tone, anemia, bone density loss, and hepatic dysfunction. Currently, several additional studies are still in the process of assessing the efficacy of combined radiation therapy with hormonal therapy, including longer duration of hormones, separate groups of patients, as well as the relative contribution of radiation therapy vs. hormones. The issue of using adjuvant hormones in patients with early stage prostate cancer has not been established. The on-going phase III trial, RTOG 94-08, is seeking to address this issue. 2.21. Morbidity of radiotherapy One of the principle reasons why patients elect radiation therapy for localized prostate cancer is the perception of reduced risk of morbidity. Although in general external beam radiation therapy is well tolerated by the majority of patients, as with any cancer treatment, radiation therapy can produce treatment-related side effects, some of which include urinary obstructive symptoms and rectal discomfort. Radiation proctitis, which may occur in severe and persistent form, may require colostomy in a small number of patients. Hartford and Zietman [96,159] have adapted data from Shipley, which nicely summarize these risks in Table 5. The acute rectal morbidity to include rectal discomfort, tenesmus, diarrhea and urinary morbidity to include frequency, nocturia, dysuria can occur in various degrees in approximately 60% of the patients treated with conventional RT and in 31% of the patients treated with conformal RT [81]. A small number of patients also may develop urinary incontinence, especially in those with a history of prior TURP. Most pa-

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Table 4 Recent results of brachytherapy / external beam radiotherapy for localized prostate cancer Authors (year)

Number of patients

Tx

Percent of T1 Stage

Gleason score 6

PSA levels

Outcome (DFS)

Ragde et al.(2000)(124,129 Ragde et al.(2000) [124,129] Grimm et al.(2001) [123] Blasko et al.(2000) [130] Blasko et al.(2000) [130] Lederman et al.(2001) [131] Brachman et al.(2000) [132] Critz et al.(2000) [133]

147 82 125 403 231 348 695 689

I-125 I-125 EBRT I-125 Pd-103or I-125 Pd-103 EBRT Pd-103or I-125 EBRT Pd-103or I-125 I-125 EBRT

22% 16% 24% 21% 21% 53% 17% 42%

0% 18% 0% 9% 7 35% 7 34% 15% 23%

66% at 12 yr 79% at 12 yr 87% at 10 yr 88% at 9 yr 79% at 9 yr 77% at 6 yr 71% at 5 yr 88% at 5 yr

Potters(2000) [134]

107

Pd-103or I-125

49%

54%

Potters(2000) [134] Storey(1999) [135] Grado et al.(1998) [136] Grado et al.(1998) [136] Stokes et al.(1997) [137]

108 193 392 62 147

Pd-103or I-125 EBRT I-125 Pd-103or I-125 Pd-103or I-125 EBRT I-125

47% 24% 6% 2% 15%

78% 13% 20% (PD) 37% (PD) 0%

8.8 mean 14.7 mean 8.1 mean 8.4 median 15.6 median 15.2 mean 11% 20 66% 10 10 median (49% 10) 10 median (49% 10) 8.6 median 7.3 median 8.7 median 10.6 mean

79% at 5 yr 84% at 5 yr 63% at 5 yr 79% at 5yr 72% at 5yr 76% at 5yr

Tx-treatment; DFS-disease free survival; yr-year; I-Iodine; Pd-Paladium; EBRT-external beam radiation therapy; PD-poorly differentiated.

tients experience these acute symptoms 2-3 weeks into therapy and recover 2-4 weeks after treatment is completed. A rare number of patients may have persistent symptoms or develop late complications 6 or more months after completion of therapy. A review of 1020 patients enrolled in two large RTOG studies showed an overall incidence of 7.3% and 3.3% for late urinary and intestinal complications that required hospitalization and 0.5% and 0.6% that required surgical interventions respectively [90]. Total dose of 70 Gy was found to be a significant factor having an impact on the incidence of late complications in patients treated with conventional radiation therapy. The volume of the rectum receiving higher doses of radiation was also correlated with higher complication [160]. Management of these side effects and complications involves proper use of medications to ameliorate the symptoms. Alpha-blockers such as Terazosin (Hytrin) and phenazopyridine (Pyridium) are effective to treat urinary symptoms. Lomotil and Imodium can control radiation-induced diarrhea and cortisone suppositories help reduce anal and rectal discomfort due to inflamed hemorrhoids. A recent literature review of retrospective and prospective data shows rates of erectile dysfunction vary widely from 6% to 84% in patients after external beam radiation therapy and 0% to 51% after brachytherapy [161]. Post-radiation impotency has been thought to be due to radiation injury to the neurovascular bundle [162] but the true etiology of sexual im-

Table 5 Radiation morbidity Number of patients Median follow-up (years) Incontinence Loss of full potency Persistent stricture Persistent hematuria Persistent rectal bleeding

331 6.1 0.4% 63.0% 1.2% 0.9% 0.6%

potence following radiation therapy is unclear and controversial. A study of penile Doppler ultrasonography demonstrated abnormal vascularity (insufficiency) in all 12 patients whose erectile function was worsened after prostate irradiation [163]. Although they had normal neurologic tests and blood testosterone levels, these patients were also noted to suffer from anxiety, depression, fear of failure and loss of masculinity. Zelefsky et al. [164] evaluated 38 patients with radiation-induced impotence after external beam radiation or brachytherapy using duplex ultrasound before and after prostaglandin injection. Arteriogenic dysfunction (peak penile flow rate 25 ml/min) was observed in 63% of patients and abnormal cavernosal dysfunction (abnormal cavernosal distensibility) in 32%. They concluded that the predominant etiology of radiationinduced impotence appeared to be related to vascular disruption induced by radiation as opposed to radiation damage of the nerve bundles. Recent data also suggest that radiationinduced impotence is highly correlated with the radiation dose delivered to the bulb of the penis [165,166]. Patients receiving 70 Gy or more to 70% of the bulb of the penis appear to be at very high risk of experiencing radiation-induced impotence. Banker [167] has demonstrated that for men who were truly sexually active prior to radiation (defined as having intercourse three or more times per month and having full erections) the chance of maintaining potency was 73% whereas for men who were borderline sexually active, the chance of maintaining potency was markedly decreased to 40%–46%. In one of the largest series from Stanford, about 86% of the 434 evaluable patients remained sexually potent 15 months after completion of radiation treatment; however, with time, about 50% remained potent at 6 years after external beam therapy and only about 30% continued to remain potent over their remaining lifetimes [168]. This possibly was due to the slow progression of radiation and natural aging effects of these patients [169]. Radiation treatment induced impotence can sometimes be effectively

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treated with intracavernosal injection of prostaglandin [170] or oral Sildenafil [171]. In patients who undergo brachytherapy, symptoms of prostatitis and urethritis to include urinary frequency, nocturia, irritation and burning often occur for several days or more and peak 3 to 6 weeks after the procedure [172,173]. Oftentimes, hematuria and bloody ejaculate due to the trauma of needle insertion and prolonged catheter use can last for several days. As with external beam radiation, patients with prior history of TURP are at higher risk of urinary incontinence. Without TURP, the risk is approximately no more than 2%. Other complications may include urethral obstruction, up to 10%, with secondary urinary retention, radiation proctitis, rectal ulceration and bleeding (1%) and sexual impotence, which is approximately 50% at 5 years. A prospective study of potency after permanent prostate brachytherapy (PPB) in 482 patients who were able to maintain an erection suitable for intercourse before treatment shows a 5-year actuarial potency rate of 76% for patients treated with PPB as monotherapy and 56% for those treated with combination external beam radiotherapy [174]. The potency rate may be higher (82% at 6 years) under experienced hands [175]. In general, most of the acute urinary and rectal symptoms resolve spontaneously and can be managed symptomatically with medications, prolonged symptoms or excessive bleeding episodes are rare. Most patients are able to return to normal life and work within a few days. As the complication rate is directly related to the organ volume receiving a high dose of radiation, the group of investigators at MSKCC has found that one salutary effect of neoadjuvant hormonal therapy is the reduction in target volume of the prostate [146]. In a study of 22 patients who received such therapy, the median percentage reduction of target volume after hormonal therapy was 25%. This correlated nicely with a 25% reduction in the rectal volume receiving a high dose of radiation. The median reduction in the volume of the bladder and rectum receiving 95% of the prescribed tumor dose was 46% and 18% respectively [147]. Other investigators also observed a significant volume reduction of prostate of 37% in average after three months of hormonal therapy prior to treatment [148]. The reduction of rectum and bladder volumes receiving 64 Gy of radiation was 20% and 34%. However, with the exception of the patients with large prostatic volume (or locally advanced disease), routine administration of androgen ablation in combination with radiotherapy for those with early stage disease should be avoided as such therapy can induce significant side effects and complications to include hot flashes, loss of libido, impotence, decrease in muscle tone, anemia, bone density loss, and hepatic dysfunction. 2.22. Quality of life Health-related quality-of-life (HRQOL) comparison between external radiation, and brachytherapy, radical prostatectomy is pivotal in the evaluation of prostate cancer therapy. A recent cross-sectional survey was conducted in 1014 patients who underwent brachytherapy, external-beam radiation, or

radical prostatectomy with age-matched controls [176]. Each therapy group reported bothersome sexual dysfunction while radical prostatectomy was more frequently associated with adverse urinary HRQOL symptoms, external beam radiation with adverse bowel HRQOL symptoms, and brachytherapy with adverse urinary and bowel HRQOL symptoms. Longterm (1 year after therapy) HRQOL evaluations after prostate brachytherapy appeared to show no benefit relative to radical prostatectomy or external-beam radiation. In addition, adjuvant hormonal therapy can be associated with significant impairment. While progression-free survival is associated with HRQOL benefits. Other studies of quality-of-life (QOL) in patients who received external beam radiation therapy or radical prostatectomy showed similar problems with urinary incontinence being more frequent among patients treated by radical prostatectomy and gastrointestinal dysfunction being more frequent after irradiation and declines in sexual function in both groups [177–179]. The general health-related quality of life outcomes were similar in both treatment groups and satisfaction with each therapy was generally high. Recently, Hanlon et al. [180] reported a long-term study of QOL in men treated with high-dose 3DCRT for prostate cancer with surveys evaluating bowel and bladder functioning, along with the AUA Symptom Problem Index and the BPH Impact Index in 139 prostate cancer patients treated with 3DCRT at Fox Chase Cancer Center. They demonstrated that QOL related to bladder function was similar to that of the normal population and only a few patients reported inconvenience from bowel symptoms as a big problem with minimal to moderate inconvenience than the normal population. However, treatment of the whole pelvis resulted in decreased QOL as defined by rectal urgency, the use of pads for bowel incontinence, and satisfaction with bowel functioning. In general, the majority of men were satisfied with their bowel and bladder functioning three to six years post treatment. 3. Conclusion Among the common modalities for the treatment of localized prostate cancer, there are no significant differences on the long-term outcome when these patients are stratified by prognostic factors. The general guidelines for treatment of prostate cancer published by the National Comprehensive Cancer Network (NCCN) have addressed the various patients’ disease issues and treatment options and delineated appropriateness of care generally accepted by most authority [181]. The long-term health outcomes may differ in urinary, bowel, and sexual functions after specific treatment. Quality of life (QOL) studies have shown gastrointestinal (GI) disturbances are more likely to occur in radiotherapy patients whereas impotence and incontinence are more commonly occur in radical prostatectomy (RP) patients. Multiple treatment options are available for the radiation therapy of prostate cancer including conventional external beam radiotherapy, three-dimensional conformal radiotherapy (3DCRT), and intensity modulated radiotherapy (IMRT), as

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well as proton or neutron beam based therapies and brachytherapy. Technological advances have continued to improve the delivery of radiotherapy. The implementation of 3D-CRT and IMRT techniques have allowed the delivery of higher tumoricidal doses and the reduction in volume of adjacent normal tissues receiving high dose of radiation resulting in a reduction of side effects and complications. An effective tumor dose of at least 74–75 Gy can be safely delivered to the prostate and periprostatic tissues with these techniques. However, the potential long-term risks of a larger volume receiving low dose of radiation is unknown as most of these patients are older, commonly in their 60s, with limited normal life-span. There are many other treatment factors that remain to be examined, such as dose to the prostate, dose per fraction, treatment of the pelvis, the radiation energy, prostatic motion during treatment, patient positioning, immobilization devices, and the use of 3-D planning for treatment. Nevertheless, prostate-specific antigen (PSA) nadirs, as well as pretreatment PSA levels, and Gleason scores remain to be the most significant prognostic factors and determine eventual outcome. Low-risk patients do well no matter which treatment they receive and high-risk patients do poorly regardless of treatment, although some dose-escalation studies have shown improved results. With continuing success in early detection, careful patient selection, paralleled by technological improvement in radiotherapy, improved long-term cure of localized prostate cancer with radiotherapy is a realistic expectation.

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