seminar-prostate

Slide 1 : Intermediate- and High-Risk Prostate Cancer Seminar june 2010 Narudom S.

Slide 2 : Epidemiology With increasing prostate-specific antigen (PSA) screening since the early 1990s, the diagnosis of high-risk disease has seen a precipitous drop from 36.6% in 1989 to 1992 to 16.0% in 1999 to 2002. Conversely, clinically nonpalpable disease (stage T1) has surged from 16.9% to 49.4%.

Slide 3 : Clinical Presentation Patients with intermediate- or high-risk prostate cancer may present with locoregional symptoms. Include nocturia, urinary frequency, urgency, decreased flow, incomplete voiding, intermittent flow, or hesitancy. More bulky primary disease may present with difficulty in passing stool or even bloody stool.

Slide 4 : Prognostic Factors and Risk Classification Schemes Prognostic factors have been clinical T stage, presenting PSA, and Gleason score. The risk classification scheme proposed by D'Amico et al. appears to be the most widely used.

Slide 5 : Low-risk : T1c to T2a, PSA =10 ng/mL and Gleason score =6. Intermediate-risk : T2b, PSA >10 but =20 ng/mL or Gleason score 7. High risk : =T2c, PSA >20 ng/mL, or Gleason score 8 to 10.

Slide 6 : Other pretreatment predictive factors. Percentage of positive biopsy cores (PPC) and PSA velocity. High PPC is associated with adverse pathologic features like extracapsular extension, seminal vesicle invasion, positive surgical margins, lymphovascular invasion, perineural invasion, and pelvic lymph node involvement.

Slide 7 : PSA velocity was calculated using linear regression modeling with at least two PSA measurements taken at least 6 months apart within 1 year prior to diagnosis. A PSA velocity >2 ng/mL per year was a significant independent predictor of PSA recurrence (p = 0.001), PCSM (p = 0.001), and overall mortality (p = 0.005). It was associated with a 12-fold increase in the risk of PCSM when adjusted for other prognostic factors.

Slide 8 : General Management Radiation Therapy Techniques Pelvic irradiation is usually treated with a four-field box The target volume usually includes the prostate, seminal vesicles, obturator, and proximal internal and external iliac nodal regions. Occasionally common iliac, para-aortic, and even perirectal nodes are included in the initial target.

Slide 9 : The traditional field borders of the anteroposterior portals are as follows: Superior at the L5–S1 interspace, inferior at 2 cm distal to the membranous urethra (defined by the apex of the urethrogram peak), 1.5 to 2 cm lateral of the pelvic brim. Corner blocks are usually placed at all four corners to limit dose to the small bowel and femoral heads.

Slide 10 : In the lateral portals, the superior and inferior borders are placed at the same point as the anteroposterior portals; The anterior border is placed at the anterior most aspect of the pubic symphysis, and the posterior border is placed at the S2–S3 interspace.

Slide 11 : Compared to conventional technique, IMRT allows unprecedented sparing of nearby critical structures like the rectum, small bowel, bladder, and femoral heads. Implementation of IMRT for pelvic radiotherapy has been somewhat hampered by the lack of guidance in delineating the nodal regions at risk.

Slide 12 : A study from Massachusetts General Hospital recommended a radial expansion of 2 cm around the iliac vessels at risk. These should include the distal 2.5 cm of the common iliacs from the iliac bifurcation, the proximal 9 cm of the external iliac vessels, and the proximal 8.5 cm of the internal iliac vessels.

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Slide 14 : In a study from UCSF, Wang et al. compared the nodal target coverage by conventional field borders with IMRT. The nodes that were contoured included the obturator, internal/external iliac, common iliac, and presacral regions. In the conventional four-field plan, only 70.3% of the nodal target volume received the prescription dose of 45 Gy, whereas 96.2% was covered in the IMRT plan (p = 0.002).

Slide 15 : Even worse, conventional field placement led to 20.2% of the nodal target volume to receive <80% of the prescription dose. The rectal and bladder volume receiving 95% of the prescribed dose were significantly reduced with IMRT, with an absolute reduction of 23% and 80%, respectively.

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Slide 18 : Prostate Motion The IMRT technique of verification of the isocenter relied on obtaining weekly port films, which only allowed comparison of bony anatomy without any consideration of the prostate and did not account for prostate motion. So…questions that have since emerged are:

Slide 19 : How much does the prostate move on a daily basis (i.e., interfractional) and during each treatment (i.e., intrafractional)? Is the positional relationship between the prostate and bony anatomy static (i.e., can bony anatomy be used as a surrogate of the prostate location)?

Slide 20 : The use of fiducial gold seed markers and daily EPI with online correction is one such strategy. In a comprehensive study from the Mayo Clinic, the inter- and intrafractional motion of the prostate and pelvic bony anatomy in 20 prostate patients, Schallenkamp et al.

Slide 21 : Determined that the prostate moved as much as 9.1 mm (mean 2.5 mm) in the superior-inferior. 16.3 mm (mean 3.7 mm) in the anterior-posterior. 15.2 mm (mean 1.9 mm) in the right-left (RL) axes. Prior to any efforts to localize the fields to the fiducial markers.

Slide 22 : In recommending a margin for setup and organ motion (i.e., CTV to PTV margin), Without fiducial marker localization, SI, AP, and RL margins of 5.1, 7.3, 5 mm, respectively, were required to cover 95% of the CTV with the prescribed dose with a 95% probability. With a daily fiducial marker localization protocol, the margins can be reduced to 2.7, 2.9, and 2.8 mm, respectively.

Slide 23 : Bony anatomy does not accurately reflect the position of the prostate. The average intrafractional displacements of the prostate and bony anatomy were 0.1 and -0.5, 0.4 and 0.4, and 0.1 and 0.3 mm in the AP, SI, and RL axes, respectively.

Slide 24 : Biologic Rationale for Prophylactic Pelvic Irradiation The incidence of clinically occult disease is unexpectedly high. Baylor College of Medicine, Shariat et al. study in patients with pT3N0 prostate cancer. Of the 199 evaluable men, 20% and 40% had positive and equivocal results, respectively.

Slide 25 : Surgical Results of Extended Pelvic Lymph Node Dissection The traditional and most common approach is to do a limited dissection. The critical difference between the two procedures is that in the limited dissection, the posterior extent is carried to the obturator nerve, whereas in the extended dissection, it is extended to include the obturator vessels and internal iliac vein.

Slide 26 : Bader et al. conducted a prospective study of the anatomic extent of pelvic nodal involvement in a cohort of 365 men who underwent an extended lymph node dissection and radical prostatectomy. Median number of nodes retrieved was 21. 24% of patients had node-positive disease, of which 49% of them had a PSA more than 20 ng/mL.

Slide 27 : The internal iliac nodes, which are not usually dissected in a limited dissection, were involved in 58% of men with node-positive disease.

Slide 28 : Heidenreich et al. reported on the incidence of lymph node involvement between standard and extended pelvic lymphadenectomy in 203 patients. There were more dissected nodes in the extended dissection group (28 vs. 11; p <0.01). There were more than twice the number of patients with positive nodes (26% and 12%; p <0.03) in the extended dissection group, with 42% of all metastases lying outside the planes of a limited dissection.

Slide 29 : In patients deemed as high risk (Gleason score 7 to 10 and PSA =10.6 ng/mL) for lymph node metastasis, 60.9% of patients had histologically positive nodes. There was no difference in pelvic lymphocele or postoperative complications between the two groups.

Slide 30 : Novel Imaging Techniques The role of lymphotropic superparamagnetic nanoparticles, given with MRI, has been recently reported. Lymph nodes that have been infiltrated by metastases will have distorted lymphatic flow, and thus will accumulate the nanoparticles.

Slide 31 : The sensitivity (90.5% vs. 35.4%; p <0.001) and specificity (97.8% vs. 90.4%; p <0.001) of MRI with superparamagnetic nanoparticles was significantly better than conventional MRI.

Slide 32 : Implications for Radiotherapy RTOG 9413 affirmed the role of whole-pelvic radiotherapy and neoadjuvant androgen suppression therapy (AST) in high-risk prostate cancer. Subgroup analysis of RTOG 9413 was recently presented, studying the volume-dependence of outcome . After stratifying by volume irradiated, the 7-year progression-free survival was 40%, 31%, and 27% in the groups that received whole-pelvic, minipelvic, and prostate-only radiotherapy (p = 0.02).

Slide 33 : There was no difference in acute grade =3 genitourinary or gastrointestinal toxicities among the three volumes.

Slide 34 : One of the most common comments regarding RTOG 9413 is whether the beneficial finding of neoadjuvant hormones and WPRT still holds true in the dose-escalation era where doses of more than 80 Gy to the prostate alone can be given safely with IMRT.

Slide 35 : Toxicity of Pelvic Intensity Modulated Radiotherapy In a study from Memorial Sloan-Kettering , The mean bowel dose was reduced by approximately 20% with 3DCRT and IMRT as compared to 2D planning (p = 0.001). The mean rectal dose was 40.4, 37.3, and 27.3 Gy, with 2D, 3DCRT, and IMRT respectively. Bladder V45 was significantly better with IMRT (87.2, 56.8, and 25.6%, respectively; p <0.001).

Slide 36 : Dose Escalation External-Beam Radiotherapy Alone M.D. Anderson Cancer Center conducted a single-institution dose-escalation phase III trial comparing 70 with 78 Gy The 6-year PSA control was 70% versus 64% in favor of the 78 Gy arm (p = 0.03), but no survival difference was observed. Subgroup analyses suggested that the benefit of dose escalation is primarily in patients with a PSA >10 ng/mL (62% vs. 43%; p = 0.012), rather than when the PSA was 10 ng/mL or less (p = 0.46) or any Gleason score.

Slide 37 : Zelefsky et al. conducted phase I and II study of dose escalation from 64.8 to 86.4 Gy to the prostate alone. Of a total cohort of 1,100 patients, there were 405 and 416 patients with intermediate- and unfavorable (i.e., high-) risk disease. None of the patients received any adjuvant hormones.

Slide 38 : In the intermediate-risk group, doses of =75.6 Gy yielded significantly better PSA control rates than doses =70.2 Gy (p = 0.008). In the unfavorable risk group, 81 Gy improved 5-year biochemical control as compared to 75.6 Gy (67% vs. 43%; p = 0.05).

Slide 39 : The overall grade 3 late rectal toxicity was 1%. In the cohort who received 75.6 Gy or greater using 3DCRT, grade 2 late rectal toxicity was 14%. Grade 3 urethral stricture or hematuria was seen in 1.5% of patients. The 5-year rate of grade 2 late urinary toxicity was 13%.

Slide 40 : Results of a dose-escalation trial from Fox Chase Cancer Center were reported. All patients (n = 839) received conformal radiotherapy without hormones to total doses of 63 to 84 Gy The group with a Gleason score of 7 to 10 and a PSA <10 ng/mL and the group with PSA 10 to 19.9 ng/mL (with any Gleason score) benefited from dose escalation. 5-year biochemical failure was 50% versus 17% in the men who received 72 to 75.9 Gy and =76 Gy (p = 0.006).

Slide 41 : Roach et al. conducted a multi-institutional study of 180 patients with Gleason score 8 to 10 disease. 5-year overall survival was 81%, 71%, and 59% after 75 to 80, 70 to 75, and <70 Gy, respectively (p = 0.04).

Slide 42 : External-Beam Radiotherapy with Brachytherapy Boost The Seattle Prostate Institute reported on the biochemical outcome of 232 consecutively treated patients with pelvic radiotherapy (45 Gy) followed by an 125I (108 Gy) or palladium 103 (103Pd) (100 Gy) brachytherapy boost. No hormones were given in this cohort.

Slide 43 : Overall, the 10-year biochemical relapse-free survival was 70%. Ten-year biochemical control was 85%, 77%, and 45% in the low-, intermediate-, and high-risk groups.

Slide 44 : McMaster University, 104 patients with T2 and T3N0 disease and negative pelvic lymphadenectomy were randomly allocated to brachytherapy plus XRT or XRT alone. The XRT-only arm received 66 Gy to the isocenter. The brachytherapy arm received 35 Gy using iridium 192 (192Ir) seeds followed by XRT of 40 Gy (total dose 75 Gy). No adjuvant hormones were given. Intermediate- and high-risk disease constituted 40% and 60% of the cohort.

Slide 45 : All patients were conventionally planned using a four-field technique that encompassed the prostate and seminal vesicles with a 2 cm margin. After a median follow-up of 8.2 years, the 5-year biochemical failure rate was significantly less in the brachytherapy arm (29% vs. 61%; p = 0.002). There was no difference in acute and late GI, GU, or sexual morbidity between the two arms.

Slide 46 : Despite the results of RTOG 9413, there has been ongoing controversy regarding whether pelvic radiotherapy or dose escalation is more important in terms of patient outcome.

Slide 47 : Clinical Trials Supporting Androgen Suppression Therapy and Radiotherapy

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Slide 54 : Toxicities of Androgen Suppression These include fatigue, weight gain, osteoporosis, depression, decreased cognitive function, erectile dysfunction, loss of libido, gynecomastia, anemia, decreased high-density lipoprotein, and hot flashes. AST significantly increased the risk of any fracture from 12.6% to 19.4%. After cessation of AST, testosterone levels may require a year or more before recovering to noncastrate levels.

Slide 55 : Duration of Androgen Suppression Therapy

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Slide 58 : Definition of Prostate-Specific Antigen Relapse after Radiotherapy PSA relapse is defined as a rise of 2 ng/mL or more above the absolute PSA nadir. This definition is only applicable to patients treated with external-beam radiotherapy with or without short-term hormonal therapy. The date of failure is taken at the time of meeting the definition and not backdated.

Slide 59 : Chemotherapy for Hormone-Refractory Prostate Cancer Mitoxantrone was one of the first agents to be shown in large phase III trials to exhibit activity toward hormone-refractory prostate cancer (HRPC). Although none of the studies demonstrated a survival advantage.

Slide 60 : Another systemic agent that has been studied is estramustine (synergistic effect with other antimicrotubule agents, such as vinblastine, etoposide, paclitaxel, and docetaxel). A phase II study, CALGB 9780 evaluated estramustine, docetaxel, and prednisone in 46 men with progressive HRPC.

Slide 61 : Beer et al. reported that weekly docetaxel reduced the PSA by at least 50% in 46% of patients, and improved pain in 48%. Of the 24 patients who had measurable disease, 3 patients had a complete response and 9 patients had a partial response.

Slide 62 : TAX-327 was a three-arm trial of 1,006 men with HRPC . All patients received prednisone and were randomized to docetaxel (75mg/m2)q 3 weeks, weekly (30mg/m2) docetaxel, or mitoxantrone (control arm). The patients in the docetaxel q 3 weeks arm, the median survival was significantly improved from 16.4 months in the control arm to 18.9 months. Pain response rates, PSA, and quality of life scores were superior in the docetaxel every 3 weeks arm.

Slide 63 : SWOG 9916, which randomized 674 men with progressive HRPC to either docetaxel every 3 weeks and estramustine (D+E) or mitoxantrone and prednisone (M+P). The median survival (17.5 vs. 15.6 months; p = 0.02), progression-free survival (6.3 vs. 3.2 months; p <0.0001), and PSA response (50% vs. 27%; p <0.0001) were significantly better in the D+E arm. In both studies, the docetaxel-based regimen had significantly higher rates of grade 3 to 4 toxicities.

Slide 64 : Chemotherapy in Locally Advanced Prostate Cancer Febbo et al.reported on a phase II study that tested 6 months of weekly docetaxel prior to surgery in 19 patients with high-risk localized prostate cancer. PSA levels decreased by at least 50% in 58% of the patients, with an average reduction of 64% after 6 months.

Slide 65 : Endorectal MRI showed that the prostate tumor volume had decreased by at least 25% and 50% in 68% and 21%, respectively, of patients.

Slide 66 : Dreicer et al. performed a phase II study of 6 weeks of preop weekly docetaxel in 29 patients with locally advanced disease. Pre- and postchemotherapy PSA were 12 and 8.4 ng/mL, respectively (p <0.03). Only 24% of patients had at least a 50% drop in PSA. In both studies, no pathologic complete responses were seen.

Slide 67 : Pettaway et al. reported that after 12 weeks of neoadjuvant ketoconazole and doxorubicin alternating with vinblastine and estramustine, 50% of the patients had an undetectable PSA yet no pathologic complete response was observed. CUOG-P01 , phase II study evaluating the pathologic effects of 6 months of neoadjuvant LHRH agonist and weekly docetaxel in 72 men with high-risk disease.

Slide 68 : 2 had a pathologic complete response and 10 had residual microfoci of cancer. Combining hormones and chemotherapy will result in 50% to 75% of patients achieving an undetectable PSA, although pathologic complete response is seldom seen.

Slide 69 : Chemotherapy and Definitive Radiotherapy Khil et al. evaluated the combination of radiotherapy and concurrent estramustine with (n = 46) or without (n = 19) vinblastine in 65 patients with locally advanced prostate cancer. By 6 weeks, PSA levels were undetectable in 86% of patients.

Slide 70 : The 5-year biochemical control rates was 46% (PSA <1.5 ng/mL), but patients with initial PSA levels <50 ng/mL had considerably better outcome of 60% to 64%. Concluded that the primary benefit of this approach appeared to be in patients with a PSA of 20 to 50 ng/mL.

Slide 71 : Zelefsky et al. reported on the outcomes of estramustine and vinblastine with 3DCRT and doses of radiotherapy (75.6 Gy). The 5-year PSA control was 34%, with the median time to relapse of 12 months. 78% remained metastasis-free, despite 22% of patients initially presenting with nodal disease. Testosterone levels recovered in 48% of patients.

Slide 72 : RTOG 9902 were presented. All patients received 8 weeks of AST then radiotherapy (70.2 Gy) and long-term adjuvant AST. Patients were then randomized to with or without four cycles of adjuvant estramustine, VP-16, and paclitaxel. Warfarin was routinely given because of the risk of DVT associated with estramustine.

Slide 73 : Grade 4 or 5 toxicities were significantly higher in the chemotherapy arm (34 vs. 0 patients). One-year actuarial rate of DVT was 8% despite intense anticoagulation. Study accrual was suspended and subsequently closed because of unacceptable risk of thromboembolic disease.

Slide 74 : In summary, cytotoxic agents have been shown to improve survival in HRPC. Presently, it remains investigational in the adjuvant setting. The premise of this multimodality approach is that chemotherapy will address hormone-insensitive cancer cells, whereas hormonal therapy will address the hormone-sensitive cells.

Slide 75 : Biochemical Failure after Radical Prostatectomy After radical prostatectomy (RP), 10-year biochemical control rates are approximately 75%. Accepted definition of biochemical failure is a postoperative PSA that exceeds 0.2 ng/mL. The difficulty in interpreting a rising PSA after surgery is determining whether it represents residual benign glands, isolated local recurrence, or distant metastases.

Slide 76 : Predictive Factors after Biochemical Failure Local versus Distant Recurrence Positive surgical margins (PSM) and extracapsular extension (ECE) are associated with increased risk of PSA recurrence and presumed local recurrence.

Slide 77 : In a multicenter study of 5,831 men treated with radical prostatectomy. The 5-year biochemical control rates were 83.8% and 53.1% for men with negative and PSM, respectively (p = 0.0001). Pound et al. reported that time to PSA recurrence =2 years after surgery, Gleason score of 8 to 10, and PSA-DT =10 months predicted for metastatic disease.

Slide 78 : Lee et al. reported findings, with a PSA-DT of <12 months and an interval of <12 months from end of radiotherapy to PSA rise as significant independent predictors of distant failure. In a multi-institutional analysis of 4,839 patients treated with radiotherapy alone, PSA nadir and time to PSA nadir were significant independent predictors of biochemical and distant failure-free survival.

Slide 79 : D'Amico et al. demonstrated that some prognostic factors could be used to predict for clinically insignificant postop PSA rises. A preop PSA <10 ng/mL, 2 ng/mL per year were associated with a postop PSA-DT <3 months.

Slide 80 : Prostate Cancer-Specific Mortality. Sandler et al.observed that a PSA-DT of less than 12 months had significantly greater PCSM. Study from Johns Hopkins found, with PSA-DT, Gleason score (=7 vs. 8 to 10), and disease-free interval (=3 vs. >3 years) independently associated with PCSM. Zhou et al. showed that a PSA-DT of less than 3 months (p <0.0001) and Gleason score of 8 to 10 (p <0.0001) were significantly associated with PCSM.

Slide 81 : Adjuvant Radiotherapy The argument for adjuvant radiotherapy (ART) is that patients with Positive surgical margins (PSM) and/or Extracapsular extension (ECE) after radical prostatectomy are at an increased risk of local recurrence.

Slide 82 : Epstein et al. reported on 617 men with clinically confined disease treated with radical prostatectomy and found that despite ECE, the 10-year progression-free survival was 58.4% to 67.7% depending on the extent. 10-year progression-free survival was 54.9% in men with PSM.

Slide 83 : The results of three large phase III trials, which evaluated the merits of adjuvant versus expectant management in postop patients with PSM and/or pT3 disease, were reported. EORTC 22911 SWOG 8794 ARO 96-02/AUO AP 09/95

Slide 84 : EORTC 22911 consisted of 1,005 men with pT2-3N0 and at least one of the following risk factors: ECE, PSM, or seminal vesicle invasion (SVI). In the ART arm, radiation was commenced at a median of 90 days postop. ART consisted of 50 Gy in 25 fractions to a large volume that encompassed the surgical limits and subclinical disease, followed by 10 Gy boost given over five fractions to a reduced margin around the prostatic bed.

Slide 85 : The protocol salvage radiotherapy dose fractionation was 70 Gy in 35 fractions. The median preop (12.3 to 12.4 ng/mL) and postop PSA (0.2 ng/mL) were not significantly different between the two arms. The median preop (12.3 to 12.4 ng/mL) and postop PSA (0.2 ng/mL) were not significantly different between the two arms.

Slide 86 : In the ART arm, 99.1% received at least the protocol dose of 60 Gy. The 5-year rates of grade 3 late toxicities was 2.6% (delayed arm) and 4.2% (ART arm; p = 0.0725).

Slide 87 : Five-year biochemical progression-free survival was significantly improved from 52.6% to 74.0% (p <0.0001) with ART, representing a 52% reduction in PSA relapse. Five-year locoregional failure was significantly lower in the ART arm (5.4% vs. 15.4%; p <0.0001). The limitations of this study were the use of conventional radiotherapy, suboptimal adjuvant dose, inclusion of patients with a persistently elevated postop PSA (10.7%), and variability in the management of relapsed patients in the delayed arm.

Slide 88 : SWOG 8794 randomly assigned 473 node-negative patients initially treated with radical prostatectomy but found to have either PSM or pT3 (ECE and/or SVI) disease to ART or observation. ART consisted of 60 to 64 Gy. The 5- and 10-year biochemical disease-free survival was significantly improved in the ART arm (61% vs. 38%, 47% vs. 23%, respectively).

Slide 89 : There was a trend toward increased 10-year metastases-free survival (83% vs. 61%) and overall survival (74% vs. 63%) in favor of ART.

Slide 90 : ARO 96-02/AUO AP 09/95 randomized 385 patients from 22 centers with pT3 or PSM to either ART (60 Gy in 2 Gy fractions) or observation. Only patients who achieved an undetectable postop PSA, ART significantly improved progression-free survival (p <0.0001). 4-year progression-free survival was 81% versus 61% in favor of ART (p <0.0001).

Slide 91 : The EORTC 22911, SWOG 8794, and ARO 96-02/AUO 09/95 provide consistent level 1 evidence that adjuvant radiotherapy is better than expectant management in terms of biochemical control, at an acceptable toxicity costs.

Slide 92 : Adjuvant versus Salvage Radiotherapy Stephenson et al. reported on the outcomes and prognostic factors of 501 men who had salvage radiotherapy after a biochemical recurrence. The 4-year progression-free survival (PFS) was 45%, and 67% attained a PSA nadir of =0.1 ng/mL. The median radiation dose was 64.8 Gy

Slide 93 : Androgen Suppression Therapy and Postoperative Radiotherapy

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Slide 95 : Postoperative Radiotherapy Dose Response Currently, adjuvant radiotherapy doses of 60 to 64 Gy and salvage radiotherapy doses of 66 to 70 Gy appear to be the most commonly used. Valicenti et al. reported on a dose-response effect in 86 patients with pT3N0 prostate cancer. The radiation dose ranged from 55 to 70.2 Gy (median dose 64.8 Gy).

Slide 96 : Among the patients with an undetectable preradiotherapy PSA, 3-year PSA control was significantly better in patients who received 61.5 Gy or more than those who received a lower dose (91% vs. 57%; p = 0.01). In the 21 patients with a preradiotherapy PSA of 0.2 to 2 ng/mL, a dose response cut-off was seen with 64.8 Gy (79% vs. 33%; p = 0.02).

Slide 97 : Anscher et al. found that a salvage dose of more than 65 Gy was associated with improved disease-free survival.

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