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The Role of Radiotherapy in Node-Positive Prostate Cancer
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The Role of Radiotherapy in Node-Positive Prostate Cancer
Review Article [1] | February 15, 2015 | Oncology Journal [2], Genitourinary Cancers [3], Prostate
Cancer [4]
By Brock R. Baker, BS [5], Jahan J. Mohiuddin, BS [6], and Ronald C. Chen, MD, MPH [7]
This article summarizes the existing literature on use of radiotherapy for node-positive prostate
cancer, as well as the associated outcomes.
Introduction
Among the 230,000 patients diagnosed with prostate cancer each year in the United States, 81%
have localized cancer, 12% have node-positive disease, and 4% have distant metastatic disease
(with the remainder unstaged).[1] While there are numerous randomized trials to guide the
management of patients with localized and metastatic cancers, few trials have specifically addressed
node-positive patients—or even included any of these patients at all. As a result, there is uncertainty
regarding the optimal treatment in this setting. Node-positive prostate cancer is categorized as
“stage IV,” but patient management likely needs to be different from that for distant metastatic
disease, and a proportion of node-positive patients are likely curable with aggressive multimodality
therapy.
This article summarizes the existing literature on use of radiotherapy for node-positive prostate
cancer, as well as the associated outcomes. Studies that examined the use of radiotherapy as
definitive treatment (discussed below and outlined in Table 1) and as adjuvant therapy after radical
prostatectomy (discussed below and outlined in Table 2) are reviewed separately.
Use of Radiotherapy as Definitive Treatment
Efficacy of androgen deprivation therapy (ADT) alone as treatment for node-positive
prostate cancer
ADT alone is one treatment option for patients with node-positive prostate cancer.[2] In the
European Organisation for Research and Treatment of Cancer (EORTC) 30846 trial, 234 men with
node-positive (pN1-3) prostate cancer were randomized from 1986 to 1998 to receive either
immediate ADT or delayed ADT (given at time of clinical progression).[3,4] Patients were confirmed
to be node-positive after lymphadenectomy, but no prostatectomy or other local treatment was
performed. ADT consisted of either orchiectomy or treatment with gonadotropin-releasing hormone
(GnRH) analog plus anti-androgen.
After a median follow-up of 13 years, the median overall survival (OS; 6.1 years with delayed ADT vs
7.6 years with immediate ADT) and 10-year prostate cancer–specific survival (44.4% for delayed ADT
vs 47.9% for immediate ADT) were not statistically significantly different between the two arms. (P
values were not reported.) Given these results, it is not clear if immediate ADT is better than a
watch-and-wait approach for these patients.
Addition of definitive radiotherapy to immediate ADT
Definitive radiotherapy significantly improves OS over ADT alone for patients with locally advanced
prostate cancer, as demonstrated by two randomized trials that compared ADT with ADT plus
radiotherapy. The absolute survival benefit from radiotherapy in these trials was 8% to 10%.[5,6]
Whether such benefit extends to patients with even more aggressive disease—node-positive
prostate cancer—has not been definitively demonstrated. However, several retrospective studies
provide support for a benefit from radiotherapy in these patients.[7-9]
In an analysis of patients treated at The University of Texas MD Anderson Cancer Center, Zagars et
al compared the outcomes of 255 patients with staging lymphadenectomy–proven pathologically
node-positive (pN+) disease who were treated with indefinite ADT alone (n = 183) vs ADT plus
radiotherapy to a median dose of 68 Gy (n = 72).[7] None of the patients had a prostatectomy. ADT
consisted of either orchiectomy (58%) or medical castration (42%, using either a GnRH agonist or
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megestrol and diethylstilbestrol).
Patients who received ADT plus radiotherapy had better 10-year OS (46% for ADT alone vs 67% for
ADT plus radiotherapy; P = .008), local control (49% vs 89%; P < .001), freedom from metastasis
(56% vs 85%; P = .006), and freedom from recurrence (25% vs 80%; P < .001); however, patients
treated with ADT alone had more aggressive cancers. On multivariate analysis, which adjusted for
Gleason score, T stage, and pretreatment prostate-specific antigen (PSA) level, the addition of
radiotherapy increased freedom from relapse or rising PSA (hazard ratio [HR] = 6.0; 95% confidence
interval [CI], 3.1–11.5), freedom from distant metastasis (HR = 2.7; 95% CI, 1.3–5.6), and OS (HR =
2.1; 95% CI, 1.2–3.9).
Two studies analyzing data from SEER (Surveillance, Epidemiology and End Results) also suggest a
survival benefit from radiotherapy. In a study from Tward et al,[8] a total of 1,100 patients with
node-positive disease diagnosed from 1988 to 2006 were included. The authors grouped both
external beam radiation therapy (EBRT) and brachytherapy patients together, and compared them
with a group that received no radiotherapy. After a median follow-up of 7.5 years, men who received
radiotherapy had greater 5-year OS (56.2% for no radiotherapy vs 67.8% for radiotherapy;
multivariate HR = 0.68; P < .01) and prostate cancer–specific survival (71.1% for no radiotherapy vs
78.1% for radiotherapy; multivariate HR = 0.67; P < .01). Another SEER analysis from Rusthoven et
al showed improved 10-year OS and prostate cancer–specific survival in patients treated with
radiotherapy vs no local therapy.[9] It is important to note that SEER data do not definitively
distinguish patients with clinical (radiographic) or pathologic (from biopsy or nodal dissection)
node-positive disease, and no information on ADT is available.
Taken together, these retrospective studies have consistently demonstrated a survival benefit from
radiotherapy compared with conservative management for node-positive prostate cancer, and
suggest that definitive therapy with radiation is reasonable to consider. However, these studies are
limited by their retrospective nature and patient selection factors that can potentially confound the
comparisons. It is important to note, however, that patients with node-positive cancer, while stage
IV, can achieve long-term survival; these retrospective studies strongly suggest that a proportion of
patients are curable with aggressive therapy. Future prospective, randomized studies are needed to
more definitively demonstrate the potential benefit of radiotherapy in node-positive disease. Current
guidelines recommend either radiotherapy plus long-term ADT (2 to 3 years) or long-term ADT alone
as treatment options.[2]
Radiotherapy with or without ADT
For patients with high-risk and locally advanced prostate cancer, multiple randomized trials have
demonstrated improved OS from adding ADT to definitive radiotherapy,[10-13] establishing this
combination as a standard of care.[2] Two of these trials included patients with node-positive
disease, and subgroup analyses of these patients provide support for adding ADT to radiotherapy in
this setting.
The Radiation Therapy Oncology Group (RTOG) 85-31 trial randomized 977 men with either T3 or
node-positive disease to EBRT alone vs EBRT plus ADT.[13] The ADT regimen was goserelin
indefinitely or until progression, and radiotherapy was 65–70 Gy as definitive treatment or 60–65 Gy
in the post-prostatectomy setting. In a subgroup analysis of the 173 patients with pathologic
node-positive disease,[14] the combined-therapy group had significantly better 5-year biochemical
control (54% combined vs 10% for radiotherapy alone; P < .0001) and distant metastasis–free
survival (P = .026; no percentages reported). OS was 72% for combined therapy vs 62% for
radiotherapy alone (P = .23), but this subgroup analysis was not adequately powered to detect a
survival difference. On multivariate analysis, radiotherapy alone compared with combined therapy
was associated with increased overall mortality (HR = 1.62; P = .03), disease-specific failure (HR =
2.12; P = .014), metastatic failure (HR = 2.54; P = .0005), and biochemical failure (HR = 3.82; P <
.0001).
Granfors et al randomized 91 patients to either EBRT alone or radiotherapy plus ADT.[15] All patients
underwent surgical lymph node staging (but not prostatectomy) prior to randomization, and 43% (n
= 39) of patients were pathologic node-positive. The radiation dose delivered was 65 Gy, and
androgen deprivation was achieved by bilateral orchiectomy. In a subgroup analysis of pathologically
node-positive patients, after a median follow-up of 9.7 years, patients who received combined
therapy had better OS compared with patients who received radiotherapy alone (log rank P = .005;
percentages not reported).
With numerous randomized trials demonstrating a survival benefit from adding ADT to radiotherapy
for patients with intermediate-risk,[16,17] high-risk, and locally advanced prostate
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cancers,[11-13,18-20] the results from these subgroup analyses of trials suggest that the benefit of
adding ADT to definitive radiotherapy likely applies to patients with node-positive prostate cancer.
Use of Radiotherapy as Adjuvant Treatment After Prostatectomy
For patients who undergo a radical prostatectomy and are found to have pathologically node-positive
disease, the optimal strategy for adjuvant management is unclear. Current guidelines include a
broad array of options, ranging from observation to ADT with and without radiotherapy,[2] but
definitive data are lacking to further guide treatment decisions.
Radical prostatectomy with immediate vs delayed ADT
Between 1988 and 1993, the Eastern Cooperative Oncology Group (ECOG) 3886 trial randomized 98
men found to be node-positive following radical prostatectomy and lymphadenectomy to either
immediate (and lifelong) or delayed ADT.[21,22] In the delayed-ADT arm, treatment was initiated on
detection of metastatic disease or symptomatic local recurrence. Therapy consisted of a GnRH
agonist or orchiectomy, as chosen by the patient. Of note, 80 of the 98 patients enrolled had
preoperative CT scans, and none had radiographic evidence of nodal metastasis. After 11.9 years
median follow-up, patients in the immediate-ADT arm had improved OS (64% vs 45% delayed ADT; P
= .04) and progression-free survival (53% vs 14% delayed ADT; P < .0001), as well as reduced
prostate cancer–specific mortality (15% vs 49% delayed ADT; P = .0004). To date, this trial provides
the only available level 1 evidence to guide adjuvant treatment decisions for pathologically
node-positive disease after radical prostatectomy.
Radical prostatectomy with immediate adjuvant radiotherapy
Adjuvant radiotherapy vs observation following radical prostatectomy improves biochemical
recurrence–free survival,[23,24] metastasis-free survival,[24,25] and possibly OS,[25] as
demonstrated by three randomized trials that included patients with locally advanced prostate
cancer (pT3 disease or positive margins). None of these trials included sufficient numbers of
node-positive patients to determine whether the benefit of adjuvant radiotherapy extended to these
patients. However, multiple retrospective studies have compared adjuvant radiotherapy with
conservative management.[26-28]
Briganti et al performed a retrospective analysis of 364 pathologically node-positive patients who
underwent radical prostatectomy, pelvic lymphadenectomy, and adjuvant ADT alone (N = 247) vs
with adjuvant radiotherapy (N = 117), between 1988 and 2003.[27] The two groups were matched
for pathologic T stage, age at surgery, pathologic Gleason score, surgical margins, number of nodes
removed, and length of follow-up. ADT used was orchiectomy (44% of patients) or GnRH agonist for
a median of 38 months.
After a median follow-up of 7.9 years, patients who received adjuvant ADT plus radiotherapy had
higher 10-year OS compared with patients who received only adjuvant ADT (55% for adjuvant ADT
only vs 74% for adjuvant ADT and radiotherapy; P < .001). Patients with combined adjuvant
treatment also had better 10-year cancer-specific survival (70% for adjuvant ADT alone vs 86% for
combined treatment; P = .004).
The magnitudes of benefit from radiotherapy to cancer-specific survival and OS were similar,
suggesting that treatment benefit is likely attributable to a reduction in cancer mortality. In subgroup
analysis, radiotherapy was associated with an OS benefit for patients with two or fewer positive
nodes (10-year survival of 54% for those treated with ADT only vs 69% for ADT and radiotherapy), as
well as for patients with more than two positive nodes (survival of 56% for ADT only vs 87% for ADT
and radiotherapy).
A more recent publication from similar authors included a retrospective analysis of 1,107 patients
with pathologically node-positive disease treated with radical prostatectomy and lymphadenectomy,
followed by adjuvant ADT; 35% also received adjuvant radiation therapy.[28] After a median
follow-up of 7.1 years, adjuvant radiation was associated with improved 8-year OS (75.1% no
radiation vs 87.6% radiation; P < .001). The authors performed further hypothesis-generating
analyses to discern whether certain patient subgroups benefited from adjuvant radiotherapy more
than others. This demonstrated a cause-specific mortality benefit in two groups: (1) patients with 3–4
positive lymph nodes (multivariate HR = 0.21; P = .02), and (2) patients with 1–2 positive nodes and
Gleason score ≥ 7, plus either pT3b/T4 stage or positive surgical margins (HR = 0.30; P = .002).
In contrast, Kaplan et al performed a SEER-Medicare analysis that did not demonstrate a benefit
from adjuvant radiotherapy. This study included 577 patients with pathologically node-positive
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disease after radical prostatectomy,[29] and compared outcomes of patients who received no
adjuvant radiotherapy vs those who received radiotherapy within 12 months of surgery. Patients in
the two groups were propensity score–matched by age, comorbidities, Gleason score, pathologic T
stage, PSA level, number of positive nodes, and receipt of adjuvant ADT (about one-third of patients
in both comparison groups). There was no statistically significant difference between the two groups
in terms of overall mortality (3.77 deaths per 100 person-years for no radiotherapy vs 5.09 deaths
per 100 person-years for adjuvant radiotherapy; P = .153) or prostate cancer–specific mortality (1.31
deaths per 100 person-years for no radiotherapy vs 2.89 deaths per 100 person-years for adjuvant
radiotherapy; P = .09).
These studies provide conflicting results, with institutional retrospective analyses demonstrating a
sizable survival benefit from adjuvant radiotherapy, but a population-based analysis showing no
benefit. Clinical trials are needed to clarify whether adjuvant radiotherapy improves survival in these
patients.
Adjuvant radiotherapy with vs without ADT
No randomized trial or retrospective study has compared adjuvant radiotherapy alone with adjuvant
radiotherapy plus ADT for node-positive patients. However, two retrospective studies of
node-negative patients suggest that adjuvant radiotherapy plus ADT may be superior to
radiotherapy alone. Ost et al analyzed 225 patients referred for adjuvant radiotherapy because of
seminal vesicle invasion, extracapsular extension, or positive margins.[30] The decision of whether
to administer ADT was left to the treating physician. On multivariate analysis, the addition of ADT to
radiotherapy was associated with improved biochemical relapse–free survival (HR = 0.4; 95% CI,
0.1–0.9; P = .02) and clinical relapse–free survival (HR = 0.1; 95% CI, 0.02–0.5; P = .004).
Another study examined the outcomes of 199 node-negative patients after prostatectomy by the
adjuvant treatment strategy: observation, radiotherapy alone, ADT alone, or radiotherapy plus
ADT.[31] Biochemical no evidence of disease was the primary endpoint, defined as PSA ≤ 0.2 ng/mL.
After a mean follow-up of 60.3 months, with observation as the reference group, radiotherapy plus
ADT was associated with improved biochemical no evidence of disease (HR = 0.15; 95% CI,
0.07–0.34; P = .001), but radiotherapy alone was not (HR = 0.64; 95% CI, 0.36–1.15; P = .13).
While these studies suggest a benefit from adding ADT to adjuvant radiotherapy for patients with
high-risk node-negative disease, further study is required to determine whether this benefit applies
to patients with node-positive prostate cancer.
Does the extent of lymph node dissection matter?
Along with a prostatectomy and standard pelvic lymphadenectomy, an extended dissection reaches
from the bifurcation of the common iliac artery superiorly to the femoral canal inferiorly. Posteriorly,
nodes are resected around the obturator nerve, obturator vessels, and internal iliac artery. The
potential benefits of an extended pelvic lymphadenectomy include more accurate staging and
increased resection of pelvic disease. In a retrospective study by Yuh et al of 406 patients with either
intermediate- or high-risk prostate cancer,[32] extended pelvic lymph node dissection (ePLND)
compared with limited PLND increased median lymph node yield (21.5 vs 7; P < .0001) and percent
node positivity (11.9% vs 3.9%; P = .003). However, there is controversy over whether the more
aggressive dissection leads to improved clinical outcomes.
Two retrospective studies suggest that there may be a benefit to ePLND. Bivalacqua et al analyzed
4,265 patients who underwent radical prostatectomy by two surgeons, one of whom performed
routine ePLND while the other performed routine limited PLND.[33] Patients who received
neoadjuvant or immediate adjuvant treatments were excluded. After a median follow-up of 10.5
years, ePLND was associated with improved 5-year biochemical recurrence–free survival (7.1% with
limited PLND vs 30.1% with ePLND; P = .018) and 10-year metastasis-free survival (22.2% with
limited PLND vs 62.2% with ePLND; P = .035). Another study by Allaf et al was of similar design,
comparing patient outcomes for ePLND (2,135 cases, performed by one surgeon) with those of
limited PLND (1,865 cases, performed by another surgeon).[34] This study showed that ePLND was
borderline-associated with improved biochemical recurrence–free survival (P = .07).
Further research is needed to more definitively address this issue. Currently, ePLND is recommended
as standard practice by the European Association of Urology and the National Comprehensive Cancer
Network.[2,35] The American Urological Association recommends that PLND be performed in
patients with a high risk of nodal involvement, and does not take a position on limited PLND vs
ePLND.[36]
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Chemotherapy in Node-Positive Prostate Cancer
Chemotherapy is a common treatment for metastatic prostate cancer.[2] However, the potential
benefit of adding chemotherapy to the treatment regimen for patients with nonmetastatic,
node-positive disease is unclear. The French Genitourinary Tumor Group (Groupe d’Etude des
Tumeurs Urogénitales [GETUG])-12 trial randomized 413 patients with high-risk or node-positive
(29%) prostate cancer (proven by staging pelvic lymph node dissection) to neoadjuvant ADT alone vs
ADT plus docetaxel and estramustine. In both arms of the study, patients received local treatment
(either prostatectomy or EBRT, decided prior to randomization) after systemic therapy. Results at a
median follow-up of 7.6 years have been presented in abstract form.[37] Chemotherapy was
associated with increased progression-free survival that was of borderline statistical significance
(62% vs 53%; P = .06). However, it is unclear if the subgroup of patients with node-positive disease
benefited more or less than the overall group. OS has not yet been reported.
Prognostic Factors in Node-Positive Patients
Several retrospective studies have examined clinical factors associated with survival outcomes in
patients with node-positive prostate cancer. In a study by Abdollah et al that included 1,107 patients
who received a radical prostatectomy and extended pelvic nodal dissection at two institutions,
patients were grouped into five prognostic groups using a regression tree approach.[28] These
groups (and associated 8-year cancer-specific mortality–free survival) were as follows:
• 1 to 2 positive nodes and Gleason score 2 to 6: 98.6% (95% CI, 95.8–100);
• 1 to 2 positive nodes, Gleason score 7 to 10, pT2/T3a, and negative surgical margins: 96.6% (95%
CI, 93.4–99.9);
• 1 to 2 positive nodes and Gleason score 7 to 10, plus either pT3b/T4 or positive margins: 86.7%
(95% CI, 83.0–90.6);
• 3 to 4 positive nodes: 85.3% (95% CI, 78.9–92.1); and
• > 4 positive nodes: 72.2% (95% CI, 62.7–83.1).
Multiple other studies have also found pathologic Gleason score,[38-40] positive surgical
margins,[38,39] number of positive nodes,[38,39] lack of adjuvant radiotherapy,[39] and pathologic
T stage[39,40] to be prognostic of cancer-specific survival in node-positive patients following
prostatectomy. A nomogram to predict 10-year cancer-specific mortality has also been developed for
node-positive patients following prostatectomy, using a Cox regression coefficient-based method
from the variables described in an analysis by Abdollah et al.[41]
Conclusion
Patients with node-positive prostate cancer represent 12% of all newly diagnosed prostate cancers in
the United States each year, and this proportion is likely to increase in the future with less use of
screening for this disease. However, this is currently an understudied patient population.
As definitive treatment, retrospective institutional and population-based analyses suggest that ADT
plus radiotherapy improves OS compared with ADT alone. In addition, secondary analyses of
prospective trial data have shown that adding ADT to definitive radiotherapy further improved
survival outcomes. These studies also consistently demonstrated that many patients with
node-positive disease can achieve long-term survival—and are likely curable—with aggressive
therapy. Given the available published evidence, current guidelines recommend either radiotherapy
with 2 to 3 years of ADT or long-term ADT alone.[2]
ECOG 3886 provides level 1 evidence to support the use of adjuvant ADT in patients who have
undergone a radical prostatectomy and lymph node dissection, and been found to have
pathologically node-positive disease. Institutional retrospective studies have demonstrated that
adding radiotherapy to ADT is associated with a sizable OS benefit, but an analysis of the
population-based SEER-Medicare data showed no significant difference in overall mortality or
cancer-specific mortality between patients who received adjuvant radiotherapy vs no radiotherapy.
No study has yet directly compared patient outcomes of adjuvant radiotherapy with vs without ADT
in these patients. Given an overall lack of relevant data addressing this question, and the sometimes
conflicting results, current guidelines recommend either observation after prostatectomy, adjuvant
ADT alone, or ADT with radiotherapy in this group of patients.[2]
At our institution, definitive radiotherapy with ADT is offered to patients with clinically node-positive
prostate cancer, and adjuvant radiotherapy with ADT after prostatectomy is offered to patients with
pathologic node-positive disease. However, discussion with patients includes acknowledging the lack
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of definitive clinical data and the uncertainty regarding optimal management of this aggressive
disease. There is a significant need for continued research to further examine the potential role of
radiotherapy as either definitive treatment, or as adjuvant treatment, for patients with node-positive
prostate cancer. Specifically, a randomized trial comparing the currently recommended treatment
options (ADT alone vs ADT plus radiotherapy) is needed, to confirm the possible survival benefit of
definitive and adjuvant radiotherapy seen in retrospective analyses. Such a trial would provide the
necessary data to guide appropriate treatment decisions for patients with this disease.
Financial Disclosure: The authors have no significant financial interest or other relationship with
the manufacturers of any products or providers of any service mentioned in this article.
Table 2: Studies Comparing Adjuvant Treatment
Options for Node-Positiv...
Table 1: Studies Comparing Primary Treatment
Options for Node-Positive...
References:
1. Fast Stats: An interactive tool for access to SEER cancer statistics. Available at
www.seer.cancer.gov/faststats. Accessed December 8, 2014.
2. Mohler JL, Kantoff PW, Armstrong AJ, et al. Prostate cancer, version 2.2014. J Natl Compr Canc
Netw. 2014;12:686-718.
3. Schröder FH, Kurth KH, Fossa SD, et al. Early versus delayed endocrine treatment of pN1-3 M0
prostate cancer without local treatment of the primary tumor: results of European Organisation for
the Research and Treatment of Cancer 30846—a phase III study. J Urol. 2004;172:923-7.
4. Schröder FH, Kurth KH, Fossa SD, et al. Early versus delayed endocrine treatment of T2-T3 pN1-3
M0 prostate cancer without local treatment of the primary tumour: final results of European
Organisation for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a
randomised controlled trial). Eur Urol. 2009;55:14-22.
5. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally
advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet.
2009;373:301-8.
6. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy
for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378:2104-11.
7. Zagars GK, Pollack A, von Eschenbach AC. Addition of radiation therapy to androgen ablation
improves outcome for subclinically node-positive prostate cancer. Urology. 2001;58:233-9.
8. Tward JD, Kokeny KE, Shrieve DC. Radiation therapy for clinically node-positive prostate
adenocarcinoma is correlated with improved overall and prostate cancer-specific survival. Pract
Radiat Oncol. 2013;3:234-40.
Page 6 of 9
The Role of Radiotherapy in Node-Positive Prostate Cancer
Published on Cancer Network (http://www.cancernetwork.com)
9. Rusthoven CG, Carlson JA, Waxweiler TV, et al. The impact of definitive local therapy for lymph
node-positive prostate cancer: a population-based study. Int J Radiat Oncol Biol Phys.
2014;88:1064-73.
10. Denham JW, Steigler A, Lamb DS, et al. Short-term androgen deprivation and radiotherapy for
locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01
randomised controlled trial. Lancet Oncol. 2005;6:841-50.
11. Roach M, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and
external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J
Clin Oncol. 2008;26:585-91.
12. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and
external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III
randomised trial. Lancet. 2002;360:103-6.
13. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive
radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol
Phys. 2005;61:1285-90.
14. Lawton CA, Winter K, Grignon D, Pilepich MV. Androgen suppression plus radiation versus
radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate:
updated results based on national prospective randomized trial Radiation Therapy Oncology Group
85-31. J Clin Oncol. 2005;23:800-7.
15. Granfors T, Modig H, Damber JE, Tomic R. Long-term follow-up of a randomized study of locally
advanced prostate cancer treated with combined orchiectomy and external radiotherapy versus
radiotherapy alone. J Urol. 2006;176:544-7.
16. Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for
localized prostate cancer. N Engl J Med. 2011;365:107-18.
17. D’Amico AV, Chen MH, Renshaw AA, et al. Androgen suppression and radiation vs radiation alone
for prostate cancer: a randomized trial. JAMA. 2008;299:289-95.
18. Denham JW, Steigler A, Lamb DS, et al. Short-term neoadjuvant androgen deprivation and
radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised
trial. Lancet Oncol. 2011;12:451-9.
19. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the
treatment of prostate cancer. N Engl J Med. 2009;360:2516-27.
20. Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group
protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced
prostate cancer. J Clin Oncol. 2008;26:2497-504.
21. Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation
after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer.
N Engl J Med. 1999;341:1781-8.
22. Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in
patients with node-positive prostate cancer after radical prostatectomy and pelvic
lymphadenectomy. Lancet Oncol. 2006;7:472-9.
23. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical
prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative
undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol. 2009;27:2924-30.
24. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced
Page 7 of 9
The Role of Radiotherapy in Node-Positive Prostate Cancer
Published on Cancer Network (http://www.cancernetwork.com)
prostate cancer: a randomized clinical trial. JAMA. 2006;296:2329-35.
25. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0
prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of
a randomized clinical trial. J Urol. 2009;181:956-62.
26. Da Pozzo LF, Cozzarini C, Briganti A, et al. Long-term follow-up of patients with prostate cancer
and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive
impact of adjuvant radiotherapy. Eur Urol. 2009;55:1003-11.
27. Briganti A, Karnes RJ, Da Pozzo LF, et al. Combination of adjuvant hormonal and radiation
therapy significantly prolongs survival of patients with pT2-4 pN+ prostate cancer: results of a
matched analysis. Eur Urol. 2011;59:832-40.
28. Abdollah F, Karnes RJ, Suardi N, et al. Impact of adjuvant radiotherapy on survival of patients
with node-positive prostate cancer. J Clin Oncol. 2014 Sep 22. [Epub ahead of print]
29. Kaplan JR, Kowalczyk KJ, Borza T, et al. Patterns of care and outcomes of radiotherapy for lymph
node positivity after radical prostatectomy. BJU Int. 2013;111:1208-14.
30. Ost P, Cozzarini C, De Meerleer G, et al. High-dose adjuvant radiotherapy after radical
prostatectomy with or without androgen deprivation therapy. Int J Radiat Oncol Biol Phys.
2012;83:960-5.
31. Bastide C, Rossi D, Lechevallier E, et al. Seminal vesicle invasion: what is the best adjuvant
treatment after radical prostatectomy? BJU Int. 2012;109:525-30; discussion 31-2.
32. Yuh BE, Ruel NH, Mejia R, et al. Standardized comparison of robot-assisted limited and extended
pelvic lymphadenectomy for prostate cancer. BJU Int. 2013;112:81-8.
33. Bivalacqua TJ, Pierorazio PM, Gorin MA, et al. Anatomic extent of pelvic lymph node dissection:
impact on long-term cancer-specific outcomes in men with positive lymph nodes at time of radical
prostatectomy. Urology. 2013;82:653-8.
34. Allaf ME, Palapattu GS, Trock BJ, et al. Anatomical extent of lymph node dissection: impact on
men with clinically localized prostate cancer. J Urol. 2004;172:1840-4.
35. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: screening,
diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65:124-37.
36. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized
prostate cancer: 2007 update. J Urol. 2007;177:2106-31.
37. Fizazi K, Laplanche A, Lesaunier F, et al. Docetaxel-estramustine in localized high-risk prostate
cancer: results of the French Genitourinary Tumor Group GETUG 12 phase III trial. J Clin Oncol.
2014;32:5005.
38. Boorjian SA, Thompson RH, Siddiqui S, et al. Long-term outcome after radical prostatectomy for
patients with lymph node positive prostate cancer in the prostate specific antigen era. J Urol.
2007;178:864-70.
39. Briganti A, Karnes JR, Da Pozzo LF, et al. Two positive nodes represent a significant cut-off value
for cancer specific survival in patients with node positive prostate cancer. A new proposal based on a
two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy,
extended pelvic lymph node dissection and adjuvant therapy. Eur Urol. 2009;55:261-70.
40. Touijer KA, Mazzola CR, Sjoberg DD, et al. Long-term outcomes of patients with lymph node
metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur
Urol. 2014;65:20-5.
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The Role of Radiotherapy in Node-Positive Prostate Cancer
Published on Cancer Network (http://www.cancernetwork.com)
41. Abdollah F, Karnes RJ, Suardi N, et al. Predicting survival of patients with node-positive prostate
cancer following multimodal treatment. Eur Urol. 2014;65:554-62.
Source URL:
http://www.cancernetwork.com/oncology-journal/role-radiotherapy-node-positive-prostate-cancer
Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/oncology-journal
[3] http://www.cancernetwork.com/genitourinary-cancers
[4] http://www.cancernetwork.com/prostate-cancer
[5] http://www.cancernetwork.com/authors/brock-r-baker-bs
[6] http://www.cancernetwork.com/authors/jahan-j-mohiuddin-bs
[7] http://www.cancernetwork.com/authors/ronald-c-chen-md-mph
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