International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Genitourinary Cancer
Postoperative Radiotherapy for Prostate Cancer: A Comparison of Four Consensus Guidelines and Dosimetric Evaluation of 3D-CRT Versus Tomotherapy IMRT Shawn Malone, M.D., F.R.C.P.C.,* Jennifer Croke, M.D.,* Nicolas Roustan-Delatour, M.D.,z Eric Belanger, M.D., F.R.C.P.C.,z Leonard Avruch, M.D., F.R.C.P.C.,x Colin Malone,* Christopher Morash, M.D., F.R.C.S.C.,y Cathleen Kayser, M.R.T.(T.),* Kathryn Underhill, B.Sc.(Hons.),* Yan Li,* Kyle Malone,* Balazs Nyiri, Ph.D.,{ and Johanna Spaans, M.Sc.* Divisions of *Radiation Oncology and yUrology and Departments of zPathology, xRadiology, and {Medical Physics, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada Received Oct 7, 2010, and in revised form Dec 21, 2011. Accepted for publication Dec 27, 2011
Summary The study evaluated four postoperative prostate cancer CTV guidelines with respect to volumetric differences and ability to meet QUANTEC and RADICALS DVH constraints. The study also evaluated potential benefits of IMRT. Significant volumetric differences exist between guidelines. The guidelines are not able to meet current QUANTEC and RADICALS dose constraints in a significant percentage of cases. IMRT results in significant OAR sparing. RADICALS dose constraints
Purpose: Despite the benefits of adjuvant radiotherapy after radical prostatectomy, approximately one-half of patients relapse. Four consensus guidelines have been published (European Organization for Research and Treatment of Cancer, Faculty of Radiation Oncology GenitoUrinary Group, Princess Margaret Hospital, Radiation Therapy Oncology Group) with the aim of standardizing the clinical target volume (CTV) delineation and improve outcomes. To date, no attempt has been made to compare these guidelines in terms of treatment volumes or organ at risk (OAR) irradiation. The extent to which the guideline-derived plans meet the dosimetric constraints of present trials or of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) trial is also unknown. Our study also explored the dosimetric benefits of intensity-modulated radiotherapy (IMRT). Methods and Materials: A total of 20 patients treated with postoperative RT were included. The three-dimensional conformal radiotherapy (3D-CRT) plans were applied to cover the guidelinegenerated planning target volumes (66 Gy in 33 fractions). Doseevolume histograms (DVHs) were analyzed for CTV/planning target volume coverage and to evaluate OAR irradiation. The OAR DVHs were compared with the constraints proposed in the QUANTEC and Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trials. 3D-CRT plans were compared with the tomotherapy plans for the Radiation Therapy Oncology Group planning target volume to evaluate the advantages of IMRT. Results: The CTV differed significantly between guidelines (p < 0.001). The European Organization for Research and Treatment of Cancer-CTVs were significantly smaller than the other CTVs (p < 0.001). Differences in prostate bed coverage superiorly accounted for the major
Reprint requests to: Shawn Malone, M.D., Department of Radiation Oncology, Ottawa Hospital Cancer Centre, 501 Smyth Rd., Ottawa, ON K1H 8L6 Canada. Tel: (613) 737-7700, ext. 70212; Fax: (613) 247-3511; E-mail:
[email protected] Int J Radiation Oncol Biol Phys, Vol. 84, No. 3, pp. 725e732, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.12.081
Supported by the Ottawa Hospital Regional Cancer Foundation. Conflict of interest: none.
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Malone et al.
should be modified to avoid reductions in CTVs.
volumetric differences between the guidelines. Using 3D-CRT, the DVHs rarely met the QUANTEC or RADICALS rectal constraints, independent of the guideline used. The RADICALS bladder constraints were met most often by the European Organization for Research and Treatment of Cancer consensus guideline (14 of 20). The tomotherapy IMRT plans resulted in significant OAR sparing compared with the 3D-CRT plans; however, the RADICALS and QUANTEC criteria were still missed in a large percentage of cases. Conclusion: Treatment volumes using the current consensus guidelines differ significantly. For the four CTV guidelines, the rectal and bladder DVH constraints proposed in the QUANTEC and RADICALS trials are rarely met with 3D-CRT. IMRT results in significant OAR sparing; however, the RADICALS dose constraints are still missed for a large percentage of cases. The rectal and bladder constraints of RADICALS should be modified to avoid a reduction in the CTVs. Ó 2012 Elsevier Inc. Keywords: Prostate cancer, Postoperative radiotherapy, Consensus guidelines, Radiotherapy and Androgen Deprivation In Combination After Local Surgery, RADICALS, Intensity-modulated radiotherapy, IMRT, Quantitative Analysis of Normal Tissue Effects in the Clinic, QUANTEC
Introduction Prostate cancer is one of the leading causes of cancer-related deaths in men worldwide. In 2010, it was estimated that almost 218,000 men were diagnosed with prostate cancer in the United States and >32,000 died of the disease (1). Although the introduction of prostate-specific antigen (PSA) testing has resulted in a stage migration toward less-advanced disease at presentation, men with locally advanced or high-risk prostate cancer still constitute approximately 17% of all newly diagnosed cases (2). In the adjuvant setting, three randomized trials have shown improved patient outcomes with the addition of radiotherapy (RT) after surgery in patients with high-risk prostate cancer (3e5). Mature results from the Southwestern Oncology Group trial 8794 have demonstrated a reduction in the 10-year risk of local failure (from 25% to 9%), distant metastasis (from 16% to 12%), and biochemical failure (from 80% to 73%) with the addition of RT after surgery in patients with a postoperative PSA level of 0.2e1.0 ng/mL, with even more pronounced benefits for adjuvant RT in patients with a lower postoperative PSA level (6). In addition, after a median of 12 years of follow-up, patients treated with adjuvant RT have also demonstrated significantly improved survival (hazard ratio, 0.72, p Z 0.023) compared with surgery alone (7). The two other randomized trials (European Organization for Research and Treatment of Cancer trial 22911 and ARO 96-02) showed improved PSA progression-free survival and improved local control for patients receiving adjuvant RT (4, 5). Despite the clear benefit of adjuvant RT, mature follow-up of the Southwestern Oncology Group 8794 trial has shown that approximately 50% of all patients relapse despite adjuvant RT, with the predominant site of failure being local (6). Both an inadequate radiation dose and poor clinical target volume (CTV) delineation have been advanced to explain the poor rates of local control. Although preliminary results have suggested that greater radiation doses in the postoperative setting improve the biochemical response (8, 9), the role of CTV delineation has not been fully explored. Furthermore, no universally accepted method is available to define the CTV after prostatectomy. To date, four uro-oncology groups have published guidelines for CTV delineation for postoperative prostate RT (10e13), with the aim of improving the outcomes of patients after surgery. To our knowledge, no attempt has been made to systematically
compare the guidelines in terms of the absolute volume irradiated or to quantify and compare the volume of normal tissue being irradiated as a function of the CTV definition applied. Although dose constraints for normal tissue exposure to the bladder and rectum have been integrated into current, large, definitive RT clinical trials (e.g., Radiotherapy and Androgen Deprivation In Combination After Local Surgery [RADICALS]), good data regarding appropriate the dose constraints in the postoperative setting are lacking. Although data have suggested that the toxicity of postoperative RT is relatively low (3e5, 14, 15), the benefit of adjuvant therapy in the context of prostate cancer treatment must be weighed against the risk of long-term side effects, which can be significant. In postoperative prostate cancer RT trials, both acute and late genitourinary (GU) and gastrointestinal (GI) toxicity have been the main side effects of adjuvant RT. Commonly reported acute radiation toxicity includes bowel urgency, frequency, and diarrhea and urinary frequency (4). Late RT-induced toxicity is somewhat less common and can include cystitis, urethral stricture, erectile dysfunction, and proctitis (manifested by rectal frequency, urgency, and bleeding) (14). Overall, the rate of acute or late grade 3 or 4 GU or GI toxicity associated with modern adjuvant or salvage RT rarely exceeds 5% (14, 16, 17). Because technology allows for greater radiation doses to be used in the adjuvant setting, a better understanding of the treatment factors potentially affecting the development of radiation-induced toxicity is required. With the aim of achieving a better understanding of how the choice of treatment guideline affects the parameters that can affect the treatment outcomes and toxicity, we compared the CTVs and the volume of normal tissue irradiated using the current consensus recommendations. As a secondary objective, the ability of the different consensus CTV guidelines to meet the rectal and bladder doseevolume histogram (DVH) constraints proposed in Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) and the ongoing RADICALS trial (Table 1) was also considered (18, 19). In brief, RADICALS is a multinational trial investigating the optimal timing of adjuvant vs. early salvage RT and the role of hormonal therapy in patients with high-risk disease (19). To the extent that the CTVs determined using different guidelines cannot meet these constraints, radiation oncologists might restrict the target volumes, possibly affecting the treatment outcomes and the ability to generalize from the results of the trial.
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Postoperative RT for PCa
Table 1 Doseevolume histogram rectal and bladder constraints used in RADICALS clinical trial Dose constraint (Gy) Rectal 30 40 50 60 66 Bladder 50 60
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by seven genitourinary radiation oncologists at the Ottawa Hospital as a part of the quality assurance rounds to ensure accurate interpretation and application of the guidelines.
Volume (%)
