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Adjuvant vs. salvage radiotherapy for patients at high risk for recurrence after radical prostatectomy
Urologic Oncology: Seminars and Original Investigations 33 (2015) 451–455
News and topics
Adjuvant vs. salvage radiotherapy for patients at high risk for recurrence after radical prostatectomy Aaron D. Falchook, M.D.a, Ronald C. Chen, M.D., M.P.H.a,b,c,* a
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC b University of North Carolina-Lineberger Comprehensive Cancer Center, Chapel Hill, NC c Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, NC Received 26 May 2015; received in revised form 25 July 2015; accepted 29 July 2015
Abstract Prostate cancer patients with adverse pathologic factors (i.e., positive surgical margin, pT3 disease) after radical prostatectomy are more likely not cured (460%) than cured by surgery alone. Adjuvant radiotherapy compared with observation reduces recurrence by 49% to 57%, may improve overall survival, and improves long-term quality of life without increased long-term patient-reported urinary or gastrointestinal tract symptoms. Despite these results, adjuvant radiotherapy is uncommonly received by patients with these adverse factors. We discuss the rationale for adjuvant therapy as part of oncologic treatment and potential reasons why patients do not receive adjuvant radiotherapy in prostate cancer. We conclude that patients need a thorough discussion regarding the potential benefits and harms of both approaches (watch and wait vs. adjuvant radiotherapy) to make an informed decision. r 2015 Elsevier Inc. All rights reserved.
Keywords: Prostate cancer; Radical prostatectomy; Adjuvant radiotherapy
Radical oncologic surgery is performed with the intent to completely remove a cancerous tumor along with potentially involved adjacent tissues, including lymph nodes, to maximize a patient’s chance for cure. Standard oncologic surgery involves removing excess organs and tissues—not just the visible tumor—to achieve this goal. In the example of prostate cancer, complete removal of the prostate is standard (not just regions where the biopsies are positive), as well as seminal vesicles and pelvic lymph nodes [1,2]— even when it is unknown if the seminal vesicles and nodes contain cancer. There are additional studies that have demonstrated that for high-risk prostate cancer, an extended lymph node dissection improves biochemical recurrencefree survival and metastasis-free survival but not overall survival compared with a standard pelvic nodal dissection [3,4]; this had led to the National Comprehensive Cancer The authors thank Dr. W. Robert Lee for his thoughtful input in the preparation of this article. * Corresponding author. Tel.: þ1-984-974-8428; fax: þ1-984-974-8619. E-mail address: [email protected] (R.C. Chen). http://dx.doi.org/10.1016/j.urolonc.2015.07.021 1078-1439/r 2015 Elsevier Inc. All rights reserved.
Network (NCCN) and European Association of Urology guidelines to recommend extended nodal dissection [2,5]. Therefore, standard oncologic surgery almost always includes intentional “overtreatment.” A patient with cancer who consents to surgery is consenting to this overtreatment to maximize the chance for a cure. Unfortunately, even after complete gross resection of a tumor, some patients still have residual microscopic disease and are not cured. Based on stage, pathologic findings including margin status, and other factors, groups of patients with a high likelihood of developing a “recurrence” (really, patients who still have microscopic disease after surgery) can be identified. Thus, the idea of adjuvant therapy—including radiotherapy and systemic therapy—is pervasive throughout oncology. Numerous trials that have included thousands of patients with a broad spectrum of disease sites have demonstrated the benefits of postoperative chemotherapy and/or radiotherapy to improve local control, reduce metastases, and improve survival in patients who are at high risk for recurrence (Table 1)—making adjuvant treatment(s) in these cancers the standard of care.
452
A.D. Falchook, R.C. Chen / Urologic Oncology: Seminars and Original Investigations 33 (2015) 451–455
Table 1 Selected randomized data demonstrating benefit of postoperative therapy for various cancer sites Cancer site
Adjuvant treatment
Benefit
Reference
Brain Breast
Radiotherapy Radiotherapy Chemotherapy Radiotherapy Radiotherapy Chemoradiotherapy Radiotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy
Improved overall survival Reduced breast cancer mortality Reduced breast cancer mortality Reduced distant recurrence Reduced local-regional recurrence Improved overall survival Reduced local recurrence Improved overall survival Improved overall survival Improved overall survival Improved overall survival
Kristiansen et al. [23] Darby et al. [24] EBCTCG [25] Rotman et al. [26] Creutzberg et al. [27] Macdonald et al. [28] Yang et al. [29] Sakuramoto et al. [30] Arriagada et al. [31] Neoptolemos et al. [32] Petersen et al. [33]
Cervix Endometrial Esophagus Extremity sarcoma Gastric Lung Pancreas Rectum
EBCTCG ¼ Early Breast Cancer Trialists' Collaborative Group.
Implied in adjuvant treatment, for any cancer, is treatment of some patients who may already be cured by surgery. There is no test or prediction tool now—or likely ever—that can identify precisely whether each patient will develop recurrence. However, if we tell a patient after radical oncologic surgery that he/she has a 60% chance of recurrence—i.e., more likely not cured than cured—most would likely choose additional treatment to maximize the chance for a cure. These principles are no different for prostate cancer. The goal of radical prostatectomy is to cure the patient. A patient receiving this most aggressive treatment option is (1) young and healthy enough to have surgery, with 410-year life expectancy and (2) consents to a degree of overtreatment at the time of surgery to maximize the chance for cure. For patients who are found to have pathologic T3 disease (extraprostatic extension or seminal vesicle invasion) or positive surgical margins, 3 randomized trials performed across multiple countries have demonstrated remarkably consistent results that 62% to 64% of patients are not cured by surgery alone; i.e., 62% to 64% of patients have residual cancer. Yet, most patients when informed of this by their urologists choose to simply wait. Fewer than 15% of patients with these adverse features receive adjuvant radiotherapy [6]—which in 3 randomized
trials consistently demonstrated the ability to reduce recurrence by 49% to 57% (Table 2) [7–9], and remains the only proven effective treatment in this setting. Further, 6% receive adjuvant androgen deprivation therapy (ADT) alone [6], which has no proven role for these patients. It is surprising that patients healthy enough to have radical surgery, are deemed to have 410-year life expectancy to potentially benefit from surgical treatment, and choose the most aggressive treatment option available to try to achieve a cure—would suddenly have a complete change of heart immediately after surgery and be satisfied with a 460% chance of recurrence. There may be several potential reasons for this, and we would like to visit each subsequently.
1. The patient and his urologist believe that his recurrence risk is lower than what has been reported in trials Indeed, high-volume surgeons may achieve better patient outcomes than surgeons with lower volume or experience. However, the very low uses of adjuvant radiotherapy in U.S. population-based patterns of care studies may suggest that most or all urologists believe that their recurrence rates are lower than the clinical trials. Is it possible that every
Table 2 Summary of 3 randomized trials evaluating adjuvant radiotherapy vs. observation after radical prostatectomy 10-Year bRFS SWOG 8794 [8] Adjuvant RT Observation EORTC 22911 [9] Adjuvant RT Observation ARO 96-02 [7] Adjuvant RT Observation
53% 26% 61% 41% 56% 35%
Recurrence HR (95% CI)
Local recurrence
Distant metastasis
10-Year OS
P o 0.001 0.43 (0.31–0.58) P o 0.001 0.49 (0.41–0.59) P o 0.001 0.51 (0.37–0.70)
P o 0.01 8% 22% P o 0.001 8% 17%
P ¼ 0.016 9% 18% P ¼ 0.94 11% 11% P ¼ 0.53 17% 14%
P ¼ 0.023 74% 66% P ¼ 0.20 77% 81% P ¼ 0.59 84%a 87%a
NR
bRFS ¼ biochemical recurrence-free survival; HR ¼ hazard ratio; OS ¼ overall survival; NS ¼ nonsignificant; RT ¼ radiotherapy; NR ¼ not reported. a Crude estimate.
A.D. Falchook, R.C. Chen / Urologic Oncology: Seminars and Original Investigations 33 (2015) 451–455
urologist is above average? Even if higher-volume urologists have 25% (or 50%) lower recurrence rates than clinical trial data, patients with adverse pathologic features still have a risk of recurrence of 48% (or 32%). 2. Adjuvant radiotherapy overtreats some patients who are already cured by surgery, and causes unnecessary adverse quality of life effects This is true but not different from adjuvant treatment of any other cancer. The number needed to treat (NNT) for adjuvant radiotherapy to prevent 1 recurrence in prostate cancer is 4.2 [10], one of the lowest numbers in all of oncology. Even with continued advances in medical science (including genetic biomarkers), NNT for adjuvant treatment would never be 1. Incidentally, NNT for primary treatment is also not 1. What is the NNT for radical prostatectomy in all patients who undergo it? (Answer: 15 based on 1 trial [11], and no survival benefit based on another trial [12]). Patients need to have an informed discussion regarding the potential benefits and harms of both options: wait and see (early salvage treatment) vs. adjuvant radiotherapy. The harm of adjuvant radiotherapy is potential urinary and gastrointestinal tract toxicity. This is well studied by the randomized trials that included more than 1,800 patients: using older radiotherapy technologies that are no longer commonly used today, 2% to 8% of patients who received adjuvant radiotherapy developed Grade 3þ urinary tract toxicity, and 0% to 2% Grade 3þ gastrointestinal tract toxicity [10]. These numbers are low (though not zero) and likely to be even lower with current standard radiotherapy technologies, which use intensity-modulated radiotherapy with daily image guidance to treat patients in this setting [13]. Although only 1 of 3 trials showed a survival benefit from adjuvant radiotherapy [8], there is also significant potential harm from watch and wait. By waiting, some patients with curable cancer become incurable, and need lifelong ADT and other treatments, which can have major effects on their quality of life. Indeed, as demonstrated by data from the Southwest Oncology Group (SWOG) 8794 randomized trial, the long-term global quality of life in patients who received adjuvant radiotherapy was better than in those patients who were observed, and long-term bowel symptoms and erectile function were no different in the 2 groups [14]. 3. Early salvage treatment is just as good as adjuvant treatment Oncologically, waiting for a recurrence (salvage treatment) can never achieve the same cure rate as that of adjuvant treatment. As per the American Society for Radiation Oncology and American Urological Association (ASTRO/AUA) guidelines, adjuvant radiotherapy for prostate cancer is defined as “the administration of radiotherapy
453
post-prostatectomy to patients at a higher risk of recurrence because of adverse pathological features prior to evidence of disease recurrence, i.e., with an undetectable prostatespecific antigen” [10]. Patients with incompletely removed cancers gradually develop (microscopic) metastatic disease over time and become incurable; those who have locally advanced disease (e.g., T3 on prostatectomy pathology) have cancers that have already demonstrated aggressiveness and may be especially vulnerable to missing the window of curability when observed. Further, as a general oncologic principle, adjuvant treatment works best when the disease burden is the lowest; when residual cancer is allowed to repopulate to the extent that it is clinically or biochemically detectable, adjuvant treatment is less likely to achieve sufficient cancer cell killing to cure patients. Thus, when a patient believes that early salvage treatment is “just as good” as adjuvant treatment—we (as physicians) do not really know that. We hope that perhaps early salvage treatment is not too much worse than adjuvant treatment. However, physicians should counsel their patients based on data rather than hope. Until currently ongoing randomized trials RAVES (Radiotherapy—Adjuvant Versus Early Salvage, NCT00860652) and RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery, NCT00541047) have published results, which will not be for several years, patients and physicians cannot confidently say that salvage radiotherapy is as good as adjuvant treatment. We do know that it is inappropriate to do active surveillance for patients with newly diagnosed high-risk or locally advanced prostate cancer. The NCCN and AUA guidelines consistently recommend treatment of patients with aggressive prostate cancers [1,2]—despite the fact that not all patients would have a survival benefit from radical prostatectomy. It seems logically inconsistent, then, to perform radical prostatectomy, confirm that indeed the patients have aggressive/locally advanced disease and are at high risk of having residual disease after surgery, and then recommend essentially active surveillance. Importantly, the urologic literature is full of studies [15–17] that demonstrated that a delay in primary treatment of aggressive prostate cancer is associated with worse patient outcomes. The oncologic principle that a delay in treatment of aggressive cancers necessarily leads to a missed curative window for a proportion of patients should apply in just the same way in the adjuvant setting. To take a breast cancer example to demonstrate this broad oncologic principle: 4 cycles chemotherapy never cures a woman with metastatic breast cancer, yet four cycles of chemotherapy given in the adjuvant setting help achieve exceedingly high cure rates for women with localized breast cancer who have not yet developed metastasis. It is important to point out that in prostate cancer, the delay from the time of prostatectomy until salvage radiotherapy can be very long. Using the Surveillance, Epidemiology, and End Results (SEER)—Medicare-linked data,
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Sheets et al. [6] demonstrated that of all patients who received postprostatectomy treatment, 37% received salvage radiotherapy more than 1 year after surgery, and 18% more than 2 years after. One cannot imagine recommending active surveillance for 1 or 2 years for a patient with high-risk or locally advanced prostate cancer, but it appears that for these same patients, it is deemed acceptable to do active surveillance after surgery and to believe that there is no oncologic consequence from this delay. One wonders if patients are truly making an informed decision. Men with newly diagnosed high-risk or locally advanced prostate cancer choosing radical prostatectomy need to be informed of their risk for having adverse pathologic risk factors, and that surgery alone may not achieve a cure. Several published nomograms can help inform patients about these risks based on diagnostic information available at the time of treatment decisionmaking, such as age, prostate-specific antigen, Gleason score, clinical stage, and percent of biopsy cores involved [18–20]. Genomic studies may also have a role in helping to identify men who would benefit from adjuvant radiotherapy —but prospective trials are needed before this could be routinely used in the clinical setting [21]. After surgery, patients who indeed have the adverse pathologic factors need to be informed about their chance for cure with surgery alone, and risks for having residual cancer. Patients with these adverse factors must be informed of the potential benefits and harms of observation. Based on best currently available evidence, adjuvant radiotherapy compared with observation reduces recurrence by 49% to 57% in these patients [7–9], causes transient urinary and gastrointestinal tract symptoms but rarely causes severe toxicity [7,9,14], and leads to improved long-term quality of life [14]. The potential harms of missing the window for cure—with consequent lifelong systemic treatment—even if years of lifelong ADT can achieve similar overall survival as that of 7 weeks adjuvant radiotherapy—in these patients with locally advanced cancers must be discussed. This is where multidisciplinary consultation and perhaps use of decision aids can help. Indeed, these considerations have been incorporated into the consensus guidelines published in 2013 by the AUA and ASTRO and endorsed by the American Society of Clinical Oncology (ASCO) [10,22]. These guidelines recommend offering adjuvant radiotherapy to all patients with adverse pathologic factors after radical prostatectomy. Prostate cancer is unique in many respects compared with other cancers. The slow-growing natural history, high prevalence of subclinical disease, and controversies related to screening and diagnosis pose challenges when designing, performing, and interpreting clinical trials. Despite these considerations, it is a fundamental oncologic principle that adjuvant therapy is beneficial for patients who undergo radical surgery that fails to remove all microscopic disease. It is also true that primary treatment (including radical prostatectomy) and adjuvant treatment always treat some
patients without direct benefit to each patient treated, but observation and delaying treatment of high-risk patients compromise cure. Work still remains to help define the optimal adjuvant treatment regimen. Although we are continuously adding to our knowledge regarding adjuvant therapy for prostate cancer, patients with high-risk features after prostatectomy must be fully informed about the potential consequences of not only adjuvant radiotherapy, but also of observation and significantly delaying radiotherapy and missing the opportunity for cure.
References [1] 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. [2] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Prostate Cancer. Version 1.2015. Available at: 〈http://www.nccn.org/ professionals/physician_gls/pdf/prostate.pdf〉 Accessed: November 28, 2014. [3] Bivalacqua TJ, Pierorazio PM, Gorin MA, Allaf ME, Carter HB, Walsh PC. 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. [4] Allaf ME, Palapattu GS, Trock BJ, Carter HB, Walsh PC. Anatomical extent of lymph node dissection: impact on men with clinically localized prostate cancer. J Urol 2004;172:1840–4. [5] 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. [6] Sheets NC, Hendrix LH, Allen IM, Chen RC. Trends in the use of postprostatectomy therapies for patients with prostate cancer: a surveillance, epidemiology, and end results Medicare analysis. Cancer 2013;119:3295–301. [7] Wiegel T, Bartkowiak D, Bottke D, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol 2014;66:243–50. [8] 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. [9] Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012;380:2018–27. [10] Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol 2013; 190:441–9. [11] Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364:1708–17. [12] Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367:203–13. [13] Corbin KS, Kunnavakkam R, Eggener SE, Liauw SL. Intensity modulated radiation therapy after radical prostatectomy: early results show no decline in urinary continence, gastrointestinal, or sexual quality of life. Pract Radiat Oncol 2013;3:138–44. [14] Moinpour CM, Hayden KA, Unger JM, et al. Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J Clin Oncol 2008;26: 112–20.
A.D. Falchook, R.C. Chen / Urologic Oncology: Seminars and Original Investigations 33 (2015) 451–455 [15] O’Brien D, Loeb S, Carvalhal GF, et al. Delay of surgery in men with low risk prostate cancer. J Urol 2011;185:2143–7. [16] Nguyen PL, Whittington R, Koo S, et al. The impact of a delay in initiating radiation therapy on prostate-specific antigen outcome for patients with clinically localized prostate carcinoma. Cancer 2005; 103:2053–9. [17] Abern MR, Aronson WJ, Terris MK, et al. Delayed radical prostatectomy for intermediate-risk prostate cancer is associated with biochemical recurrence: possible implications for active surveillance from the SEARCH database. Prostate 2013;73:409–17. [18] Eifler JB, Feng Z, Lin BM, et al. An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011. BJU Int 2013;111:22–9. [19] Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. J Urol 2005;173:1938–42. [20] Kattan MW, Yu C, Salomon L, Vora K, Touijer K, Guillonneau B. Development and validation of preoperative nomogram for disease recurrence within 5 years after laparoscopic radical prostatectomy for prostate cancer. Urology 2011;77:396–401. [21] Den RB, Yousefi K, Trabulsi EJ, et al. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol 2015;33:944–51. [22] Freedland SJ, Rumble RB, Finelli A, et al. Adjuvant and salvage radiotherapy after prostatectomy: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 2014; 32:3892–8. [23] Kristiansen K, Hagen S, Kollevold T, et al. Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 1981;47:649–52. [24] Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast
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[33]
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cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707–16. EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–717. Rotman M, Sedlis A, Piedmonte MR, et al. A phase III randomized trial of postoperative pelvic irradiation in Stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2006;65: 169–76. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;355:1404–11. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345:725–30. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–20. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351–60. Neoptolemos JP, Stocken DD, Tudur Smith C, et al. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J Cancer 2009; 100:246–50. Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012;3:CD004078.
News and topics
Adjuvant vs. salvage radiotherapy for patients at high risk for recurrence after radical prostatectomy Aaron D. Falchook, M.D.a, Ronald C. Chen, M.D., M.P.H.a,b,c,* a
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC b University of North Carolina-Lineberger Comprehensive Cancer Center, Chapel Hill, NC c Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, NC Received 26 May 2015; received in revised form 25 July 2015; accepted 29 July 2015
Abstract Prostate cancer patients with adverse pathologic factors (i.e., positive surgical margin, pT3 disease) after radical prostatectomy are more likely not cured (460%) than cured by surgery alone. Adjuvant radiotherapy compared with observation reduces recurrence by 49% to 57%, may improve overall survival, and improves long-term quality of life without increased long-term patient-reported urinary or gastrointestinal tract symptoms. Despite these results, adjuvant radiotherapy is uncommonly received by patients with these adverse factors. We discuss the rationale for adjuvant therapy as part of oncologic treatment and potential reasons why patients do not receive adjuvant radiotherapy in prostate cancer. We conclude that patients need a thorough discussion regarding the potential benefits and harms of both approaches (watch and wait vs. adjuvant radiotherapy) to make an informed decision. r 2015 Elsevier Inc. All rights reserved.
Keywords: Prostate cancer; Radical prostatectomy; Adjuvant radiotherapy
Radical oncologic surgery is performed with the intent to completely remove a cancerous tumor along with potentially involved adjacent tissues, including lymph nodes, to maximize a patient’s chance for cure. Standard oncologic surgery involves removing excess organs and tissues—not just the visible tumor—to achieve this goal. In the example of prostate cancer, complete removal of the prostate is standard (not just regions where the biopsies are positive), as well as seminal vesicles and pelvic lymph nodes [1,2]— even when it is unknown if the seminal vesicles and nodes contain cancer. There are additional studies that have demonstrated that for high-risk prostate cancer, an extended lymph node dissection improves biochemical recurrencefree survival and metastasis-free survival but not overall survival compared with a standard pelvic nodal dissection [3,4]; this had led to the National Comprehensive Cancer The authors thank Dr. W. Robert Lee for his thoughtful input in the preparation of this article. * Corresponding author. Tel.: þ1-984-974-8428; fax: þ1-984-974-8619. E-mail address: [email protected] (R.C. Chen). http://dx.doi.org/10.1016/j.urolonc.2015.07.021 1078-1439/r 2015 Elsevier Inc. All rights reserved.
Network (NCCN) and European Association of Urology guidelines to recommend extended nodal dissection [2,5]. Therefore, standard oncologic surgery almost always includes intentional “overtreatment.” A patient with cancer who consents to surgery is consenting to this overtreatment to maximize the chance for a cure. Unfortunately, even after complete gross resection of a tumor, some patients still have residual microscopic disease and are not cured. Based on stage, pathologic findings including margin status, and other factors, groups of patients with a high likelihood of developing a “recurrence” (really, patients who still have microscopic disease after surgery) can be identified. Thus, the idea of adjuvant therapy—including radiotherapy and systemic therapy—is pervasive throughout oncology. Numerous trials that have included thousands of patients with a broad spectrum of disease sites have demonstrated the benefits of postoperative chemotherapy and/or radiotherapy to improve local control, reduce metastases, and improve survival in patients who are at high risk for recurrence (Table 1)—making adjuvant treatment(s) in these cancers the standard of care.
452
A.D. Falchook, R.C. Chen / Urologic Oncology: Seminars and Original Investigations 33 (2015) 451–455
Table 1 Selected randomized data demonstrating benefit of postoperative therapy for various cancer sites Cancer site
Adjuvant treatment
Benefit
Reference
Brain Breast
Radiotherapy Radiotherapy Chemotherapy Radiotherapy Radiotherapy Chemoradiotherapy Radiotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy
Improved overall survival Reduced breast cancer mortality Reduced breast cancer mortality Reduced distant recurrence Reduced local-regional recurrence Improved overall survival Reduced local recurrence Improved overall survival Improved overall survival Improved overall survival Improved overall survival
Kristiansen et al. [23] Darby et al. [24] EBCTCG [25] Rotman et al. [26] Creutzberg et al. [27] Macdonald et al. [28] Yang et al. [29] Sakuramoto et al. [30] Arriagada et al. [31] Neoptolemos et al. [32] Petersen et al. [33]
Cervix Endometrial Esophagus Extremity sarcoma Gastric Lung Pancreas Rectum
EBCTCG ¼ Early Breast Cancer Trialists' Collaborative Group.
Implied in adjuvant treatment, for any cancer, is treatment of some patients who may already be cured by surgery. There is no test or prediction tool now—or likely ever—that can identify precisely whether each patient will develop recurrence. However, if we tell a patient after radical oncologic surgery that he/she has a 60% chance of recurrence—i.e., more likely not cured than cured—most would likely choose additional treatment to maximize the chance for a cure. These principles are no different for prostate cancer. The goal of radical prostatectomy is to cure the patient. A patient receiving this most aggressive treatment option is (1) young and healthy enough to have surgery, with 410-year life expectancy and (2) consents to a degree of overtreatment at the time of surgery to maximize the chance for cure. For patients who are found to have pathologic T3 disease (extraprostatic extension or seminal vesicle invasion) or positive surgical margins, 3 randomized trials performed across multiple countries have demonstrated remarkably consistent results that 62% to 64% of patients are not cured by surgery alone; i.e., 62% to 64% of patients have residual cancer. Yet, most patients when informed of this by their urologists choose to simply wait. Fewer than 15% of patients with these adverse features receive adjuvant radiotherapy [6]—which in 3 randomized
trials consistently demonstrated the ability to reduce recurrence by 49% to 57% (Table 2) [7–9], and remains the only proven effective treatment in this setting. Further, 6% receive adjuvant androgen deprivation therapy (ADT) alone [6], which has no proven role for these patients. It is surprising that patients healthy enough to have radical surgery, are deemed to have 410-year life expectancy to potentially benefit from surgical treatment, and choose the most aggressive treatment option available to try to achieve a cure—would suddenly have a complete change of heart immediately after surgery and be satisfied with a 460% chance of recurrence. There may be several potential reasons for this, and we would like to visit each subsequently.
1. The patient and his urologist believe that his recurrence risk is lower than what has been reported in trials Indeed, high-volume surgeons may achieve better patient outcomes than surgeons with lower volume or experience. However, the very low uses of adjuvant radiotherapy in U.S. population-based patterns of care studies may suggest that most or all urologists believe that their recurrence rates are lower than the clinical trials. Is it possible that every
Table 2 Summary of 3 randomized trials evaluating adjuvant radiotherapy vs. observation after radical prostatectomy 10-Year bRFS SWOG 8794 [8] Adjuvant RT Observation EORTC 22911 [9] Adjuvant RT Observation ARO 96-02 [7] Adjuvant RT Observation
53% 26% 61% 41% 56% 35%
Recurrence HR (95% CI)
Local recurrence
Distant metastasis
10-Year OS
P o 0.001 0.43 (0.31–0.58) P o 0.001 0.49 (0.41–0.59) P o 0.001 0.51 (0.37–0.70)
P o 0.01 8% 22% P o 0.001 8% 17%
P ¼ 0.016 9% 18% P ¼ 0.94 11% 11% P ¼ 0.53 17% 14%
P ¼ 0.023 74% 66% P ¼ 0.20 77% 81% P ¼ 0.59 84%a 87%a
NR
bRFS ¼ biochemical recurrence-free survival; HR ¼ hazard ratio; OS ¼ overall survival; NS ¼ nonsignificant; RT ¼ radiotherapy; NR ¼ not reported. a Crude estimate.
A.D. Falchook, R.C. Chen / Urologic Oncology: Seminars and Original Investigations 33 (2015) 451–455
urologist is above average? Even if higher-volume urologists have 25% (or 50%) lower recurrence rates than clinical trial data, patients with adverse pathologic features still have a risk of recurrence of 48% (or 32%). 2. Adjuvant radiotherapy overtreats some patients who are already cured by surgery, and causes unnecessary adverse quality of life effects This is true but not different from adjuvant treatment of any other cancer. The number needed to treat (NNT) for adjuvant radiotherapy to prevent 1 recurrence in prostate cancer is 4.2 [10], one of the lowest numbers in all of oncology. Even with continued advances in medical science (including genetic biomarkers), NNT for adjuvant treatment would never be 1. Incidentally, NNT for primary treatment is also not 1. What is the NNT for radical prostatectomy in all patients who undergo it? (Answer: 15 based on 1 trial [11], and no survival benefit based on another trial [12]). Patients need to have an informed discussion regarding the potential benefits and harms of both options: wait and see (early salvage treatment) vs. adjuvant radiotherapy. The harm of adjuvant radiotherapy is potential urinary and gastrointestinal tract toxicity. This is well studied by the randomized trials that included more than 1,800 patients: using older radiotherapy technologies that are no longer commonly used today, 2% to 8% of patients who received adjuvant radiotherapy developed Grade 3þ urinary tract toxicity, and 0% to 2% Grade 3þ gastrointestinal tract toxicity [10]. These numbers are low (though not zero) and likely to be even lower with current standard radiotherapy technologies, which use intensity-modulated radiotherapy with daily image guidance to treat patients in this setting [13]. Although only 1 of 3 trials showed a survival benefit from adjuvant radiotherapy [8], there is also significant potential harm from watch and wait. By waiting, some patients with curable cancer become incurable, and need lifelong ADT and other treatments, which can have major effects on their quality of life. Indeed, as demonstrated by data from the Southwest Oncology Group (SWOG) 8794 randomized trial, the long-term global quality of life in patients who received adjuvant radiotherapy was better than in those patients who were observed, and long-term bowel symptoms and erectile function were no different in the 2 groups [14]. 3. Early salvage treatment is just as good as adjuvant treatment Oncologically, waiting for a recurrence (salvage treatment) can never achieve the same cure rate as that of adjuvant treatment. As per the American Society for Radiation Oncology and American Urological Association (ASTRO/AUA) guidelines, adjuvant radiotherapy for prostate cancer is defined as “the administration of radiotherapy
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post-prostatectomy to patients at a higher risk of recurrence because of adverse pathological features prior to evidence of disease recurrence, i.e., with an undetectable prostatespecific antigen” [10]. Patients with incompletely removed cancers gradually develop (microscopic) metastatic disease over time and become incurable; those who have locally advanced disease (e.g., T3 on prostatectomy pathology) have cancers that have already demonstrated aggressiveness and may be especially vulnerable to missing the window of curability when observed. Further, as a general oncologic principle, adjuvant treatment works best when the disease burden is the lowest; when residual cancer is allowed to repopulate to the extent that it is clinically or biochemically detectable, adjuvant treatment is less likely to achieve sufficient cancer cell killing to cure patients. Thus, when a patient believes that early salvage treatment is “just as good” as adjuvant treatment—we (as physicians) do not really know that. We hope that perhaps early salvage treatment is not too much worse than adjuvant treatment. However, physicians should counsel their patients based on data rather than hope. Until currently ongoing randomized trials RAVES (Radiotherapy—Adjuvant Versus Early Salvage, NCT00860652) and RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery, NCT00541047) have published results, which will not be for several years, patients and physicians cannot confidently say that salvage radiotherapy is as good as adjuvant treatment. We do know that it is inappropriate to do active surveillance for patients with newly diagnosed high-risk or locally advanced prostate cancer. The NCCN and AUA guidelines consistently recommend treatment of patients with aggressive prostate cancers [1,2]—despite the fact that not all patients would have a survival benefit from radical prostatectomy. It seems logically inconsistent, then, to perform radical prostatectomy, confirm that indeed the patients have aggressive/locally advanced disease and are at high risk of having residual disease after surgery, and then recommend essentially active surveillance. Importantly, the urologic literature is full of studies [15–17] that demonstrated that a delay in primary treatment of aggressive prostate cancer is associated with worse patient outcomes. The oncologic principle that a delay in treatment of aggressive cancers necessarily leads to a missed curative window for a proportion of patients should apply in just the same way in the adjuvant setting. To take a breast cancer example to demonstrate this broad oncologic principle: 4 cycles chemotherapy never cures a woman with metastatic breast cancer, yet four cycles of chemotherapy given in the adjuvant setting help achieve exceedingly high cure rates for women with localized breast cancer who have not yet developed metastasis. It is important to point out that in prostate cancer, the delay from the time of prostatectomy until salvage radiotherapy can be very long. Using the Surveillance, Epidemiology, and End Results (SEER)—Medicare-linked data,
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Sheets et al. [6] demonstrated that of all patients who received postprostatectomy treatment, 37% received salvage radiotherapy more than 1 year after surgery, and 18% more than 2 years after. One cannot imagine recommending active surveillance for 1 or 2 years for a patient with high-risk or locally advanced prostate cancer, but it appears that for these same patients, it is deemed acceptable to do active surveillance after surgery and to believe that there is no oncologic consequence from this delay. One wonders if patients are truly making an informed decision. Men with newly diagnosed high-risk or locally advanced prostate cancer choosing radical prostatectomy need to be informed of their risk for having adverse pathologic risk factors, and that surgery alone may not achieve a cure. Several published nomograms can help inform patients about these risks based on diagnostic information available at the time of treatment decisionmaking, such as age, prostate-specific antigen, Gleason score, clinical stage, and percent of biopsy cores involved [18–20]. Genomic studies may also have a role in helping to identify men who would benefit from adjuvant radiotherapy —but prospective trials are needed before this could be routinely used in the clinical setting [21]. After surgery, patients who indeed have the adverse pathologic factors need to be informed about their chance for cure with surgery alone, and risks for having residual cancer. Patients with these adverse factors must be informed of the potential benefits and harms of observation. Based on best currently available evidence, adjuvant radiotherapy compared with observation reduces recurrence by 49% to 57% in these patients [7–9], causes transient urinary and gastrointestinal tract symptoms but rarely causes severe toxicity [7,9,14], and leads to improved long-term quality of life [14]. The potential harms of missing the window for cure—with consequent lifelong systemic treatment—even if years of lifelong ADT can achieve similar overall survival as that of 7 weeks adjuvant radiotherapy—in these patients with locally advanced cancers must be discussed. This is where multidisciplinary consultation and perhaps use of decision aids can help. Indeed, these considerations have been incorporated into the consensus guidelines published in 2013 by the AUA and ASTRO and endorsed by the American Society of Clinical Oncology (ASCO) [10,22]. These guidelines recommend offering adjuvant radiotherapy to all patients with adverse pathologic factors after radical prostatectomy. Prostate cancer is unique in many respects compared with other cancers. The slow-growing natural history, high prevalence of subclinical disease, and controversies related to screening and diagnosis pose challenges when designing, performing, and interpreting clinical trials. Despite these considerations, it is a fundamental oncologic principle that adjuvant therapy is beneficial for patients who undergo radical surgery that fails to remove all microscopic disease. It is also true that primary treatment (including radical prostatectomy) and adjuvant treatment always treat some
patients without direct benefit to each patient treated, but observation and delaying treatment of high-risk patients compromise cure. Work still remains to help define the optimal adjuvant treatment regimen. Although we are continuously adding to our knowledge regarding adjuvant therapy for prostate cancer, patients with high-risk features after prostatectomy must be fully informed about the potential consequences of not only adjuvant radiotherapy, but also of observation and significantly delaying radiotherapy and missing the opportunity for cure.
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