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Invited presentations of the latest cancer research www.ajho.com
These arTicles are available from The January 2010 issue of aJho: Jonathan B. Strauss; Monica Morrow;
Balazs Halmos and Joshua R. Sonett
William Small, Jr.
Is there a role for perioperative therapy in locally advanced Predicting involvement of 4 or more lymph nodes: Does it esophageal cancer? Case closed, time to move on Rohini K. Hernandez; Henrik T. Sørensen;
Hoshang Farhad; Maria-Victoria Orcurto;
Lars Pedersen; Jacob Jacobsen;
Michael Montemurro; Serge Leyvraz; John O.
Timothy L. Lash
Prior
Tamoxifen treatment and the risk of deep venous Metabolic imaging with 18F-FDG-PET in patients with imatinib-resistant gastrointestinal stromal tumor Hillard M. Lazarus and Nathan A. Berger
Farhana Sharmeen and David M. Jackman
Treating chronic lymphocytic leukemia in the elderly— Bevacizumab in non-small cell lung cancer Kandace P. McGuire; Alfredo A. Santillan;
Krishnansu S. Tewari
Paramjeet Kaur; Tammi Meade; Jateen Parbhoo;
A critical need for reappraisal of therapeutic options for women Morgan Mathias; Corinne Shamehdi;
with metastatic and recurrent cervical carcinoma: Commentary Michelle Davis; Daniel Ramos; Charles E. Cox
on Gynecologic Oncology Group Protocol 204 Mastectomy vs breast conservation: Mastectomy on the rise Breast Cancer
ask The exPerT
Larissa Nekhlyudov and Laurel A. Habel
Women with ductal carcinoma in situ are not getting follow-
up mammograms after breast-conserving surgery
PERSPECTIVE
Quality of Life after Dose-Escalated Radiation Therapy for Prostate Cancer Mark W. McDonald, MD, and Peter A.S. Johnstone, MD, FACR Department of Radiation Oncology, Indiana University,Indianapolis, Indiana, and Midwest ProtonRadiotherapy Institute, Bloomington, Indiana Men with localized prostate cancer have a variety of treatment choices and can expect similar disease con-trol and survival outcomes from radical prostatectomy, external beam radiation therapy, and interstitialprostate brachytherapy.1,2 In addition to cancer control, treatment-related side effects and quality-of-life end-points are influential in most men when deciding between therapeutic modalities.3 In the past decade, results of several randomized trials have shown a statistically signifi- between men treated on the conventional and high-dose arms. Patients cant improvement in biochemical disease control for patients treated treated on the conventional dose arm were more often concerned about with high-dose external beam radiation therapy (74–79.2 Gy) com- their cancer control and more often expressed regret about their treatment pared to conventional dose radiation therapy (64–70.2 Gy).4–8 These decision. Unfortunately, patient-reported data were not collected at baseline trials also have generally observed an increased but clinically accept- or at any other time point, which hinders interpretation of the data.
able rate of acute gastrointestinal (GI) toxicity with high-dose radia- Prospective patient-reported quality-of-life assessment was conducted in the tion. Not surprisingly given the study sizes and still limited follow- Dutch CKTO 69-10 randomized prostate dose escalation trial,5 and prelim- up, none have yet shown an improvement in cancer-specific or over- inary results at 3 years of follow-up have similarly indicated no difference in all survival. Notably lacking until recently have been patient-report- quality-of-life outcomes between patients randomized to conventional (68 ed toxicity and quality-of-life outcomes.
Since quality-of-life measures appear to worsen with longer follow-up Talcott et al suggest that their results may validate the ability of proton time,9,10 to properly gauge the therapeutic benefit of dose escalation, it is therapy to deliver a higher and more efficacious dose to the prostate with- important to assess for increased toxicity in the high-dose radiation arms as out increasing long-term toxicity. Although a significant portion of the radi- these trial data continue to mature. The recent report by Talcott et al11 pro- ation dose was delivered with x-rays in PROG 9509, and there was no arm vides long-term patient-reported outcomes from a randomized prostate treated with dose-escalated x-ray radiation alone for comparison, these dose-escalation trial. All living patients enrolled in the Proton Radiation results provide valuable long-term patient-reported toxicity outcomes after Oncology Group (PROG) 9509 randomized controlled trial of radiation dose-escalated proton therapy for prostate cancer. Proton therapy is a form dose escalation in prostate cancer were contacted and asked to answer a of conformal external beam radiation therapy that uses accelerated protons questionnaire using validated assessments of urinary and bowel complica- instead of high-energy x-rays. Unlike x-rays, protons can be modulated to tions, sexual function, and disease-focused quality of life. PROG 9509 ran- have a defined stopping point in tissue where they deposit most of their domized 393 patients with clinically localized stage T1b to T2b prostate energy.14 This peak dose deposition at the termination of the proton path is cancer with prostate-specific antigen (PSA) less than 15 ng/mL treated with known as the Bragg peak and allows treatment with protons to effectively external beam radiation therapy alone to a total dose of either 70.2 Gy or stop dose in tissue at a given point and eliminate dose to tissues beyond that 79.2 Gy.4 All patients received 50.4 Gy with conformal x-ray therapy and point. Protons also have a sharp beam penumbra, meaning that on the lat- either 19.8 Gy or 28.8 Gy equivalent with proton therapy. At a median fol- eral edges of the beam, the dose drops from full intensity to zero intensity low-up time of nearly 9 years, patients treated on the high-dose radiation arm were significantly more likely to have local control and biochemical dis- With its unique physical properties, proton therapy for prostate cancer ease control with a hazard ratio for local failure of 0.57.12 Physician assess- can be delivered through two lateral fields, eliminating the entrance and exit ment found no difference in acute or late genitourinary (GU) toxicity nor dose to normal tissues outside of these fields that would otherwise be tra- in late GI toxicity, although acute GI toxicity of grade 2 or higher was seen versed with multi-field x-ray treatment. Formal comparisons of proton ther- in 64% of patients in the high-dose arm compared to 45% in the conven- apy and intensity-modulated (x-ray) radiation therapy (IMRT) for prostate cancer have quantified the reductions in radiation dose to normal tissues, Eighty-three percent of the patients remaining alive (n = 280) respond- such as the bladder and rectum, achieved with proton therapy.16,17 ed to the questionnaire at a median time of 9.4 years after treatment. Results Given the correlation of dose to normal structures and resultant tox- showed no difference in patient-reported GU, GI, or sexual function icity, quality radiation treatment planning and delivery are expected to The authors were invited to provide this commentary on the research findings reported in Talcott JA, Rossi C,Shipley WU, et al. Patient-reported long-term outcomes after conventional and high-dose combined proton andphoton radiation for early prostate cancer. JAMA. 2010;303:1046–1053.
88 • AJHO MAY 2010;9(3) • WWW.AJHO.COM Perspective / Quality of life after radiation therapy for prostate cancer Sagittal views of a 7-field IMRT photon planfor prostate cancer (left) and a proton plan(right), prescribed to 79.2 Gy. The bladder(yel ow) and rectum (blue) are outlined. Arectal bal oon fil ed with radiopaque fluid isused to increase rectal sparing and for pro-static immobilization. Both modalitiesclosely conform the high-dose volume (redarea) to the target, while the proton planreduces the volume of normal tissuesreceiving low and moderate doses of radia-tion (blue and green, here 20 Gy to 50 Gy).
Images courtesy of Chee-Wai Cheng, PhD,Midwest Proton Radiotherapy Institute.
translate into lower rates of toxicity and fewer adverse effects on quality the MRC RT01 randomised controlled trial. Lancet Oncol. 2007;8:475–487.
of life. Indeed, subsequent correlation of the PROG 9509 patient-report- 9. Johnstone PA, Gray C, Powell CR. Quality of life in T1-3N0 prostate cancer ed outcomes with radiation dosimetry found a significant association patients treated with radiation therapy with minimum 10-year follow-up. Int J Radiat between increased dose to the anterior rectal wall and subsequent GI dys- Oncol Biol Phys. 2000;46:833–838.
function, independent of the prescribed dose to the prostate.18 10. Gardner BG, Zietman AL, Shipley WU, Skowronski UE, McManus P. Late nor- These quality-of-life data from the Dutch CKTO 69-10 and PROG mal tissue sequelae in the second decade after high dose radiation therapy with com- 9509 randomized trials, at short- and long-term follow-up, respectively, bined photons and conformal protons for locally advanced prostate cancer. J Urol.
provide the first confirmation that the improved disease control obtained with dose-escalated radiation therapy can be achieved without 11. Talcott JA, Rossi C, Shipley WU, et al. Patient-reported long-term outcomes after increased patient-reported late toxicity. Corollary data confirm that conventional and high-dose combined proton and photon radiation for early prostate quality radiation planning matters, and techniques and interventions cancer. JAMA. 2010;303:1046–1053.
that reduce dose to normal tissue sparing can translate into improved 12. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional- dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american col- lege of radiology 95-09. J Clin Oncol. 2010;28:1106–1111.
1. Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam 13. Al-Mamgani A, van Putten WL, van der Wielen GJ, Levendag PC, Incrocci L.
radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed Dose Escalation and Quality of Life in Patients with Localized Prostate Cancer implantation, or combined seeds/external beam radiotherapy for stage T1-T2 Treated with Radiotherapy: Long-Term Results of the Dutch Randomized Dose- prostate cancer. Int J Radiat Oncol Biol Phys. 2004;58:25–33.
Escalation Trial (CKTO 96-10 Trial). Int J Radiat Oncol Biol Phys. 2010 Apr 24.
2. Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized 14. Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–491.
prostate cancer. Ann Intern Med. 2008;148:435–448.
15. Urie MM, Sisterson JM, Koehler AM, Goitein M, Zoesman J. Proton beam 3. Zeliadt SB, Ramsey SD, Penson DF, et al. Why do men choose one treatment over penumbra: effects of separation between patient and beam modifying devices. Med another?: a review of patient decision making for localized prostate cancer. Cancer.
16. Trofimov A, Nguyen PL, Coen JJ, et al. Radiotherapy treatment of early-stage 4. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs prostate cancer with IMRT and protons: a treatment planning comparison. Int J high-dose conformal radiation therapy in clinically localized adenocarcinoma of the Radiat Oncol Biol Phys. 2007;69:444–453.
prostate: a randomized controlled trial. JAMA. 2005;294:1233–1239.
17. Chera BS, Vargas C, Morris CG, et al. Dosimetric study of pelvic proton radio- 5. Peeters ST, Heemsbergen WD, Koper PC, et al. Dose-response in radiotherapy for therapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys.
localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol. 2006;24:1990–1996.
18. Nguyen PL, Chen RC, Hoffman KE, et al. Rectal Dose-Volume Histogram 6. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M.D. Anderson Parameters Are Associated with Long-Term Patient-Reported Gastrointestinal randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys.
Quality of Life After Conventional and High-Dose Radiation for Prostate Cancer: A Subgroup Analysis of a Randomized Trial. Int J Radiat Oncol Biol Phys. 2010 Mar 5.
7. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with con- formal protons compared with conventional dose irradiation using photons alone. Int Disclosures: The authors disclose no relevant conflicts of interest. J Radiat Oncol Biol Phys. 1995;32:3–12.
Correspondence address: Mark W. McDonald, MD, 535 Barnhill Dr, RT 041, 8. Dearnaley DP, Sydes MR, Graham JD, et al; for the RT01 collaborators. Escalated- Indianapolis, IN 46202; e-mail: mwmcdona@iupui.edu. dose versus standard-dose conformal radiotherapy in prostate cancer: first results from WWW.AJHO.COM • AJHO MAY 2010;9(3) • 89

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