From owner-radoncjc@net.bio.net Thu Nov 2 02:54:39 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 83CB617A88; Thu, 2 Nov 2000 02:54:36 +0000 (GMT) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 6028) id CDADA17A7E; Thu, 2 Nov 2000 02:54:34 +0000 (GMT) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 6024) id 08DE917A7E; Thu, 2 Nov 2000 02:48:46 +0000 (GMT) Received: from mail1.radiological.com (mail1.radiological.com [206.13.127.226]) by mercury.hgmp.mrc.ac.uk (Postfix) with SMTP id 95500415DE for ; Thu, 2 Nov 2000 02:48:38 +0000 (GMT) Received: from RASROUTING-Message_Server by mail1.radiological.com with Novell_GroupWise; Wed, 01 Nov 2000 18:48:16 -0800 Message-Id: X-Mailer: Novell GroupWise 5.5.4 From: "Brian Goldsmith MD" To: Subject: November 2000 Internet Radiation Oncology Journal Club (IROJC) Content-Disposition: inline Newsgroups: bionet.radoncjc Date: Thu, 2 Nov 2000 02:54:34 +0000 (GMT) Sender: owner-radoncjc@net.bio.net Precedence: bulk November 2000 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 66th collection of references suggested for attention and discussion by the IROJC's Board of Editors: Sarah Donaldson, M.D. Editor, Pediatric Radiation Oncology Robert Foote, M.D. Editor, Head and Neck / Skin Radiation Oncology Abram Recht, M.D. Editor, Breast Radiation Oncology Rich Hoppe, M.D. Editor, Reticuloendothelial System Radiation Oncology Dan Petereit, M.D. Editor, Gynecological Radiation Oncology Andrew Turrisi, M.D. Editor, Lung and Mediastinum Radiation Oncology Joel Tepper, M.D. Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology Mack Roach, M.D. Editor, Genitourinary Radiation Oncology Glenn Bauman, M.D. Editor, Central Nervous System Radiation Oncology Rod Withers, M.D., D.Sc. Editor, Radiobiology James Hayman, M.D. Editor, Health Services Research George Chen, Ph.D. Editor, Radiation Biophysics ----------------------------------------------------- You're encouraged to critically review this set of references and respond by posting your comments to the IROJC readership at radoncjc@net.bio.net. ----------------------------------------------------- Peds: Donaldson 11/00 AU: Beck MN, Balmer A, Dessing C, Pica A, Munier F. TI: First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. SO: J Clin Oncol. 2000 Aug;18(15):2881-7. URL: http://www.jco.org/cgi/content/full/18/15/2881 ID: PMID: 10920136 UI: 20381199 Abstract: PURPOSE: To evaluate the efficacy of first-line chemotherapy (CT) in preventing external-beam radiotherapy (EBR) and/or enucleation in patients with retinoblastoma (Rbl). PATIENTS AND METHODS: Twenty-four patients with newly diagnosed unilateral or bilateral Rbl received CT associated with local treatment (LT). Two to five courses of etoposide and carboplatin were administered at 3- to 4-week intervals, depending on tumor response, and were completed each time by LT. RESULTS: Tumor response was observed in all eyes. Twenty-one of 24 patients showed a complete response (CR) that persisted at a median follow-up (FU) of 31 months (range, 4 to 41 months). Among the three patients who relapsed, two were lost to FU and one died of progressive disease. CR was achieved by CT and LT alone in 15 (71.4%) of 21 patients with less advanced disease (groups I to III). Six other patients with advanced disease (groups IV and V) experienced treatment failure and needed salvage treatment by EBR and/or enucleation. The difference between the two patient groups with regard to disease stage was statistically significant (P <.0001). EBR could be avoided in 13 (68.4%) of 19 patients, who presented with groups I to III (15 eyes) and group V (one eye) disease, whereas enucleation could be avoided in only two (40%) of five. CONCLUSION: CT combined with intensive LT is effective in patients with groups I to III Rbl, permitting the avoidance of EBR in the majority of these young children and, thus, reducing the risk of long-term sequelae. This is in contrast with the disappointing results for patients with groups IV and V Rbl, in whom EBR and/or enucleation was needed. Editor's comments: The enormous concern of secondary malignancies occuring in survivors of retinoblastoma have pushed clinicians to look for alternative treatments other than external beam radiotherapy. This paper touts chemotherapy with etoposide and carboplain followed by local treatment (cryotherapy, photocoagulation, plaque radiotherapy, and thermochemotherapy) as successful management for babies with Group I,II, and III retinoblastoma. The authors acknowledge this approach is ineffective for the more common presentation with Group IV and V disease. The endpoint in this study is the avoidance of external beam irradiation. However enucleation was not avoided in all patients, and there is no attention given to the late effects of etoposide (a known carcinogen) or carboplatin. My own interpretation of the data brings me to a slightly different conclusion from that of the authors. We all acknowledge the concern of secondary cancers, many of which can be attributed to the Rb gene. Early stage retinoblastoma may well be controlled by well focused external beam irradiation as delivered by protons, or intensity modulated radiotherapy and give the same response rate, and avoid the recognized sequelae of systemic chemotherapy. It is not yet appropriate to assume that all children with retinoblastoma require chemotherapy. ****************** Head/Neck/Skin: Foote 11/00 No Reference Selected ****************** Breast: Recht 11/00 AU: Kuhl CK; Schmutzler RK; Leutner CC; Kempe A; Wardelmann E; Hocke A; Maringa M; Pfeifer U; Krebs D; Schild HH. TI: Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. SO: Radiology 2000 Apr;215(1):267-79 URL: http://radiology.rsnajnls.org/cgi/content/full/215/1/267 ID: PMID: 10751498 UI: 20217202 Abstract: PURPOSE: To compare magnetic resonance (MR) imaging with conventional imaging in screening high-risk women. MATERIALS AND METHODS: This prospective trial included 192 asymptomatic and six symptomatic women who, on the basis of personal or family history or genetic analysis, were suspected or proved to carry a breast cancer susceptibility gene. RESULTS: Fifteen breast cancers were identified: nine in the 192 asymptomatic women (six in the first and three in the second screening round) and six in the symptomatic patients. Concerning the asymptomatic women, four of the nine breast cancers were detected and correctly classified with mammography and ultrasonography (US) combined; another two cancers were visible as well-circumscribed masses and were diagnosed as fibroadenomas. MR imaging allowed the correct classification and local staging of all nine cancers. In 105 asymptomatic women with validation of the 1st-year screening results, the sensitivities of mammography, US, and MR imaging were 33%, 33% (mammography and US combined, 44%), and 100%, respectively; the positive predictive values were 30%, 12%, and 64%, respectively. CONCLUSION: The accuracy of MR imaging is significantly higher than that of conventional imaging in screening high-risk women. Difficulties can be caused by an atypical manifestation of hereditary breast cancers at both conventional and MR imaging and by contrast material enhancement associated with hormonal stimulation. Editor's comments: This is the largest study to date of the use of MRI in the screening setting that I know of. It is particularly importnat because of the "high risk" population being imaged. One interesting observation was the atypical presentation of many of the tumors, which may reflect the presence of BRCA1/2 mutations (see pp.275-6). If confirmed by other studies, then many of our patients may become candidates for this approach. ****************** RES: Hoppe 11/00 AU: Hjalgrim H, Askling J, Sorensen P, Madsen M, Rosdahl N, Storm HH, Hamilton-Dutoit S, Eriksen LS, Frisch M, Ekbom A, Melbye M. TI: Risk of Hodgkin's Disease and Other Cancers After Infectious Mononucleosis. SO: J Natl Cancer Inst. 2000 Sep 20;92(18):1522-1528. URL: http://jnci.oupjournals.org/cgi/content/full/92/18/1522 ID: PMID: 10995808 UI: No Cit. ID assigned Abstract: BACKGROUND: Infectious mononucleosis, which is caused by the Epstein-Barr virus, has been associated with an increased risk for Hodgkin's disease. Little is known, however, about how infectious mononucleosis affects long-term risk of Hodgkin's disease, how this risk varies with age at infectious mononucleosis diagnosis, or how the risk for Hodgkin's disease varies in different age groups. In addition, the general cancer profile among patients who have had infectious mononucleosis has been sparsely studied. METHODS: Population-based cohorts of infectious mononucleosis patients in Denmark and Sweden were followed for cancer occurrence. The ratio of observed-to-expected numbers of cancers (standardized incidence ratio [SIR]) served as a measure of the relative risk for cancer. SIRs of Hodgkin's disease in different subsets of patients were compared with the use of Poisson regression analysis. All statistical tests including the trend tests were two-sided. RESULTS: A total of 1381 cancers were observed during 689 619 person-years of follow-up among 38 562 infectious mononucleosis patients (SIR = 1.03; 95% confidence interval [CI] = 0.98-1.09). Apart from Hodgkin's disease (SIR = 2.55; 95% CI = 1.87-3.40; n = 46), only skin cancers (SIR = 1.27; 95% CI = 1.13-1.43; n = 291) occurred in statistically significant excess. In contrast, the SIR for lung cancer was reduced (SIR = 0.71; 95% CI = 0.58-0.86; n = 102). The SIR for Hodgkin's disease remained elevated for up to two decades after the occurrence of infectious mononucleosis but decreased with time since diagnosis of infectious mononucleosis (P: for trend <.001). The SIR for Hodgkin's disease tended to increase with age at diagnosis of infectious mononucleosis (P: for trend =.05). Following infectious mononucleosis, the SIR for Hodgkin's disease at ages 15-34 years was 3.49 (95% CI = 2.46-4.81; n = 37), which was statistically significantly higher than the SIR for any other age group (P: for difference =.001). CONCLUSION: The increased risk of Hodgkin's disease after the occurrence of infectious mononucleosis appears to be a specific phenomenon. ****************** GYN: Petereit 11/00 AU: Shin CH, Schorge JO, Lee KR, Sheets EE. TI: Conservative management of adenocarcinoma in situ of the cervix. SO: Gynecol Oncol. 2000 Oct;79(1):6-10. URL: http://www.idealibrary.com/links/citation/0090-8258/79/6 ID: PMID: 11006022 UI: 20463069 Abstract: Objective. The purpose of this study was to determine the method of treatment and outcome of women with cervical adenocarcinoma in situ (AIS). Methods. Following institutional review board approval, all women diagnosed with cervical AIS from 1987 to 1999 were identified. Data were retrospectively collected by record review and correspondence with medical providers. Results. Of 132 women treated with cone biopsy for AIS, 95 (72%) were managed conservatively after cold knife cone or loop electrical excisional procedure alone; 37 (28%) eventually underwent hysterectomy. The median age of diagnosis was 29 years (range, 17-47) in the conservative management group and 40 years (range, 25-72) in the hysterectomy group (P < 0.0001). Seventy-four percent were nulliparous in the conservative group compared with 27% in the hysterectomy group (P < 0.0001). Of the 95 conservatively managed patients, 92 obtained negative margins; three were followed despite positive or unevaluable margins. During a median follow-up of 30 months, 9 women required evaluation for follow-up abnormalities after cone biopsy with negative margins. None had pathologic evidence of recurrent AIS. Twenty-three infants were delivered. Hysterectomy was generally performed for undesired fertility or persistently positive cone margins. One woman required hysterectomy for recurrent AIS. Thirteen (62%) of twenty-one hysterectomy specimens had residual AIS following cone biopsy with positive or unevaluable margins; 1 (6%) of 16 had residual AIS following cone biopsy with negative margins (P < 0.0001). No patient developed invasive adenocarcinoma. Conclusions. Younger women with cervical AIS may be effectively treated with cone biopsy alone if negative margins can be achieved. Copyright 2000 Academic Press. AND AU: Hopkins MP. TI: Adenocarcinoma in situ of the cervix-The margins must Be clear. SO: Gynecol Oncol. 2000 Oct;79(1):4-5. URL: http://www.idealibrary.com/links/citation/0090-8258/79/4 ID: PMID: 11006021 UI: 20463068 Editor's comments: Shin et al. described their experience in managing woman with adenocarincoma in Situ (AIS) in a conservative fashion. This retrospective study reviewed the outcome of 95 women who were managed conservatively by either a cold knife cone or loop electrical excisional procedure (LEEP). Thirty-seven patients eventually underwent a hysterectomy for a variety of reasons. The authors correlated initial cone biopsy margin status with residual disease. Sixty-two percent of patients with positive/unevaluable margins had residual AIS in the hysterectomy specimen, whereas only 6% of patients did with negative margins. No patients in their study developed an invasive adenocarcinoma. Criticisms of this study include relatively short follow-up for some patients and lost to follow-up for others. The sentinel issue for these patients is whether they can be safely managed in a conservative fashion so as to preserve their reproductive potential. It is critical that gynecologic oncologists who manage these patients carefully review the pathology slides. For example, a small focus of AIS identified on a cone biopsy has a much smaller risk for recurrence than extensive multifocal disease - even though both patients may achieve negative margins. In the current study, the risk for residual disease in the hysterectomy specimen was only 6% if negative margins were achieved. The number quoted in the literature typically has been 25%. It is important to note that the risk is not 0%. Therefore, these patients need close surveillance. For patients who are not interested in child bearing or who are post-menopausal, standard therapy consists of a TAH/BSO. For women who want to maintain fertility, this study does add to a growing body of evidence that conservative management for AIS is feasible. Also, a cold knife cone is preferable since the margins are "charred" with the LEEP procedure. As the incidence of cervical adenocarcinomas continues to increase, there most likely be an increase in AIS as well. These reproductive issues will become increasingly common as women continue to delay child-bearing. Lastly, as radiation oncologists, you might be questioning the relevance of this review for your practice. In short, as gynecologic oncologists become increasingly involved in radiation issues, we need to become cognizant of their issues - especially in a tumor board setting. ****************** Lung/Mediastinum: Turrisi 11/00 AU: Andre F, Grunenwald D, Pignon JP, Dujon A, Pujol JL, Brichon PY, Brouchet L, Quoix E, Westeel V, Le Chevalier T. TI: Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. SO: J Clin Oncol. 2000 Aug;18(16):2981-9. URL: http://www.jco.org/cgi/content/full/18/16/2981 ID: PMID: 10944131 UI: 20402472 Abstract: PURPOSE: Patients who suffer from non-small-cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (N2) belong to a heterogeneous subgroup of patients. We analyzed the prognosis of patients with resected N2 NSCLC to propose homogeneous patient subgroups. PATIENTS AND METHODS: The present study comprised 702 consecutive patients from six French centers who underwent surgical resection of N2 NSCLC. Initially, two groups of patients were defined: patients with clinical N2 (cN2) and those with minimal N2 (mN2) disease were patients in whom N2 disease was and was not detected preoperatively at computed tomographic scan, respectively. RESULTS: The median duration of follow-up was 52 months (range, 18 to 120 months). A multivariate analysis using Cox regression identified four negative prognostic factors, namely, cN2 status (P <. 0001), involvement of multiple lymph node levels (L2+; P <.0001), pT3 to T4 stage (P <.0001), and no preoperative chemotherapy (P <. 01). For patients treated with primary surgery, 5-year survival rates were as follows: mN2, one level involved (mN2L1, n = 244): 34%; mN2, multiple level involvement (mN2L2+, n = 78): 11%; cN2L1 (n = 118): 8%; and cN2L2+ (n = 122): 3%. When only patients with mN2L1 disease were considered, the site of lymph node involvement according to the American Thoracic Society numbering system had no prognostic significance (P =.14). Preoperative chemotherapy was associated with a better prognosis for those with cN2 (P <.0001). Five-year survival rates were 18% and 5% for cN2 patients treated with and without preoperative chemotherapy, respectively. CONCLUSION: This study has identified homogeneous N2 NSCLC prognostic subgroups and suggests different therapeutic approaches according to the subgroup profile. Editor's comments: While the abstract of this study might turn you off, the report is really quite important. The abstract refers to mN2 and cN2 -- the text describes the distinction of minimal versus clinical, and then L-1 and L-2+ are levels of lymph nodes, the former being a solitary station, the latter multi level. We regularly struggle with the issue of who might be benefited from surgery if we know that a an N-2 node is positive. The Mountain system has its mole-holes and molehills. We stumble here. The paper centers on the nodal issues, but it alludes to the size of the tumor -- it is a factor in their final analysis, but Mountain doesn't value this. The heritage of operation on N-2 nodes rests on the shoulders of three thoracic surgical pillars -- Naruke from Japan, Pearson from Canada and Martini from Memorial. This paper reveres these giants, but treads carefully along the furrow it digs between those where operations seem to succeed and those where it is less successful. At the end, we remain unsure but enlightened. The clinical N-2 patients do not do very well with surgery, and maybe a little better with chemotherapy, but perhaps no better than with chemoradiotherapy alone. An intergroup trial tackles this question, has >400 patients entered, BUT it intertwines without stratification cN2 and mN2, L1 and L2+, and tumors ranging from tiny to huge -- before this paper, there was more disparate opinion about these factors, and the paper nicely deals with the varying reports in the discussion. The case for chemotherapy in these individual groups is mixed and weakened by tiny size of the samples. In one report, if one analyzes by pneumonectomy, particularly right pneumonectomy, it is more powerful as a negative predictor of survival than the benefit of the chemotherapy. The largest trial, DePierre, has not been positive at interim for stage III-a patients. The US Intergroup trial has more patients than any other trial, but this paper prepares us to look at these factors in analyzing the results of this study when accrual is complete. The trial has been slowed due to bad press, the new drug craze, and the inability of good doctors to honestly admit to themselves and then their patients that they do not know that a resection is beneficial or harmful. Cisplatin Etoposide plus 45 Gy before surgery is the dowdy experimental arm, and the same drugs to 61 Gy without surgery is the control arm (Yes, there is a pilot and experience showing its results). Many moan that the radiotherapy dose is too low, but there is little data to support any single higher dose of radiotherapy(although many of us use it off study in practice, and a few are trying to formally study this). I eagerly anticipate the completion of this trial, but we will need to look at the variables described in this paper to see if they hopefully are randomly distributed because we did not stratify for them. This study will be flawed, but it is the best we have. The problem here is the heterogeneity of III-a. Studies select patients, and those that get surgery are vastly those with PS 1 or less. The Mountain system is hard to apply prospectively. It is hard to look at a case and say in the pre-operative tumor board whether it is cN2 or mN2 sometimes. Maybe PET will help. I worry that the series that we have and are collecting may not reflect the population. This issue is one of the most troubling of our lives, and I'm not sure we are solving it just yet. ****************** GI / Soft Tissue Sarcoma: Tepper 11/00 AU: Hoff PM, Janjan N, Saad ED, Skibber J, Crane C, Lassere Y, Cleary KR, Benner S, Randolph J, Abbruzzese JL, Pazdur R. TI: Phase I study of preoperative oral uracil and tegafur plus leucovorin and radiation therapy in rectal cancer. SO: J Clin Oncol. 2000 Oct 15;18(20):3529-34. URL: http://www.jco.org/cgi/content/full/18/20/3529 ID: PMID: 11032595 UI: 20487648 Abstract: PURPOSE: Preoperative combined-modality therapy for rectal cancer may allow for sphincter preservation, while decreasing recurrence rates and improving the overall prognosis. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may reduce costs and complications associated with protracted infusions of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with preoperative radiation and determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFT plus LV in this setting. PATIENTS AND METHODS: Patients with tumor-node-metastasis stage II or III rectal cancer received escalating doses of UFT (starting at 250mg/m(2)/d, with 50-mg/m(2)/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). The UFT and LV combination was given 5 days per week concurrently with a 5-week course of preoperative radiation totaling 45 Gy (1.8 Gy/fraction). Surgery was performed 4 to 6 weeks after radiation and was followed by four 35-daycycles of fixed doses of UFT and LV (28 days of therapy each cycle). RESULTS: Fifteen patients were treated, and 13 received the full preoperative chemotherapy. All planned radiation was delivered successfully. The MTD of UFT with radiation was 350 mg/m(2)/d with 90 mg/d of LV. Diarrhea was the DLT. Sphincter-preserving surgery was performed in 12 of 14 patients. One patient had progressive disease before surgery. Pathologic evaluation of 14 resected specimens showed a complete response in three cases. CONCLUSION: Preoperative chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated. Editor's comments: There is nothing earth shaking in this article, but it does present information on an issue which will be quite important to the practicing radiation oncologist- the incorporation of the newer generation of oral fluoropyrimidines into combined modality regimens. Most of these agents- such as xeloda, UFT, and ethinyluracil are designed for oral administration and to mimic as closely as possible the pharmacologic profile of continuous infusion 5-FU. Thus, there is little expectation that these agents would have a superior outcome in terms of tumor control, but they would be more convenient in avoiding the use of a pump and central venous access. This study determined the MTD of UFT and leucovorin with radiation.y Unfortunately, some investigators, including these, have made some assumptions which I think may not be valid. First, they have implicitly assumed that the value of the fluoropyrimidine is entirely for radiosensitization and that there is no value of the drug alone either for local or systemic disease. Thus, they have proceeded to a 5-day administration schedule in order to decrease toxicity. This may be a valid approach (toxicity is certainly less for the same dose/day), but it is not clear that with continuous infusion therapy that this will maximize total anti-tumor effect. If that were so, maybe the drug should just be given for a half-hour before and after RT. Studies have shown that the systemic effect is important in rectal cancer and this benefit could be lost with a 5-day schedule. Also, the MTD determined in this study cannot be applied to a seven day/week drug administration schedule. The second error that I fear will be made, is that the timing of the oral drug relative to the radiation therapy will not be defined. If one looks at the pharmacology of these oral agents, they do not give a smooth distribution of drug throughout the day as is obtained with continuous infusion 5-FU. Rather, there are pronounced peaks and valleys. It is likely that radiation sensitization will be effected by the timing of the two modalities. In this paper, no description is given of the timing of the administration, although I suspect that the benefit would be maximized if the drug were given approximately 1-2 hours prior to the RT. Third, one must keep in mind that the various oral agents are not exactly the same. They have differing modes of activatio, or effect drug metabolism in differing ways so that it will not be appropriate to move from one to the other. Tumor response might vary as well as toxicity. I suspect that in a few years continuous infusion 5-FU through a pump will be a thing of the past. However, at the present time we don't know how to optimize therapy when combined with RT. ****************** GU: Roach 11/00 No Reference Selected ****************** CNS: Bauman 11/00 Editors Note: This month's journal club selection comes "live" from Boston at the 42nd Annual Meeting of ASTRO! I tried to group a few papers from the oral CNS sessions according to themes: Theme 1: Stereotactic radiosurgery boost for patients with multiple brain metastases Preliminary Report of RTOG 9508: A Phase III Trial Comparing Whole Brain Irradiation Alone Versus Whole Brain Irradiation Plus Stereotactic Radiosurgery for Patients with Two or Three Unresected Brain Metastases P. W. Sperduto1, C. Scott2, D. Andrews3, M. Schell4, M. Werner-Wasik3, W. Demas5, J. K. Ryu6, J. Fontanesi7, M. Rotman8 and W. Curran3 1Methodist Hospital, Minneapolis, MN, 2Radiation Therapy Oncology Group, Philadelphia, PA, 3Thomas Jefferson University , Philadelphia, PA, 4University of Rochester, Rochester, NY, 5Akron City Hospital, Akron, OH, 6University of California at Davis, Davis, CA, 7Wayne State University, Detroit, MI, 8State University of New York, Brooklyn, New York Purpose: To compare the survival, local control, toxicity, cause of death and quality-of-life in patients with two or three brain metastases treated with whole brain radiation therapy (WBRT) plus stereotactic radiosurgery (SRS) (Grp 1) versus WBRT alone (Grp 2). Methods: Between 3/96 and 5/99, 144 patients with 2 or 3 brain metastases were randomized. The solitary metastasis component of RTOG 9508 remains open to accruel and thus is not a part of this analysis. 139 patients are evaluable. Grp 1 received 37.5 Gy WBRT in 15 fractions followed by SRS (15-24 Gy) whereas Grp 2 received 37.5 Gy WBRT only. The pre-treatment patient characteristics were well balanced between the two groups. Mini-mental status exams, Karnofsky Performance Status (KPS) and steroid requirements were monitored throughout follow-up to assess quality-of-life. Results: Survival, cause of death and toxicity data are available and are described below. There was no significant difference (NSD) in overall survival. The median survival time (MST) for Groups 1 and 2 was 5.3 and 6.7 months respectively (p=0.59). Similarly, there was NSD in survival between groups 1 and 2 when analyzed by RPA class (1 vs. 2), KPS (70-80 vs. 90-100) or age, however the prognostic value of RPA class and KPS appear to have been confirmed. Similarly, there was NSD in survival for patients with controlled versus uncontrolled primary tumors. There was a linear relationship between survival and neurologic function status regardless of treatment group. The cause of death data show NSD between Groups 1 and 2. The percentage of patients who were reported by the treating institution to have died from the brain metastases for Groups 1 and 2 was 33% and 35% respectively. Furthermore, there was NSD between the cause of death in patients with controlled versus uncontrolled primary tumors. Analysis of failure rates within the target volume showed a slight but not statistically significant advantage in the WBRT + SRS group (21% vs 37% at one year, p=0.107). Regarding toxicity, there were no grade 4 or 5 toxicities in either group. The rate of acute grade 3 toxicities in Groups 1 and 2 was 3/69 (4%) and 0/70 (0%), respectively. The rate of late grade 3 toxicities in Groups 1 and 2 was 2/39 (5%) and 1/51 (2%). All grade 3 toxicites were of neurologic origin. Conclusions: There is no survival advantage in patients with 2 or 3 brain metastases when treated with WBRT plus SRS versus WBRT alone. Cause of death patterns are similar between the two groups. Local control at one year was slightly better for the WBRT plus SRS group. This possible benefit will be analyzed in conjunction with quality-of-life data and central review of tumor response. The treatment was well tolerated. Randomized Treatment of Brain Metastasis with Gamma Knife Radiosurgery, Whole Brain Radiotherapy or Both P. B. Chougule, M. Burton-Williams, S. Saris, Z. Zheng, B. Ponte, G. Noren, L. Alderson, G. Friehs, D. Wazer and M. Epstein Rhode Island Hospital/Brown University, Providence, RI Introductions: Although whole brain radiotherapy (WBRT) offers adequate palliation to approximately 60% of patients, the overall survival is a dismal four months. Gamma Knife radiosurgery (GK) offers better local control of treated lesions, but its superiority in overall survival over WBRT remains unknown. To assess local control of treated lesions, control of brain disease and overall survival, we initiated a three-arm prospective randomized clinical trial comparing GK alone, WBRT alone or both. Treatment randomization was stratified by primary tumor site. Methods: Of the 109 patients enrolled in the study, 96 received protocol recommended therapy and are evaluable. Treatment randomization was GK alone: 36, GK + WBRT: 37 and WBRT: 31 patients. Primary sites included non-small cell lung cancer (NSCLC): 62, breast cancer: 12, colorectal cancer: 4, unknown: 7 and miscellaneous: 11 patients. Eligibility criteria included patients with <3 lesions, tumor volume <30 ccs and minimum life expectancy of three months were included. The treatment dose was: GK 30 Gy to the tumor margin, WBRT 30 Gy + GK 20 Gy to the margin, and WBRT 30 Gy in 10 fractions for GK, GK + WBRT and WBRT arms respectively. Fifty-one patients underwent surgical resection of large, symptomatic lesions prior to randomization. All patients had pre and post treatment neurological exam and MRI at GK treatment and at 6 weeks, 3, 6 and 12 month follow-up. Results: The overall median survival was 7, 5 and 9 months for the GK, GK + WBRT and WBRT arms respectively. The local control was 87%, 91%, and 62% for GK, GK + WBRT and WBRT alone arms respectively, suggesting that the two radiosurgery arms were superior. However, the occurrence of new brain lesions was lower (43%, 19% and 23% for GK, GK + WBRT and WBRT alone respectively) in the two arms receiving WBRT. Regardless of treatment group, the local control and survival for patients who had surgical resection of brain metastases was 88% and 9 months compared to 73% and 6 months for those without resection suggesting some benefit of surgery. This survival benefit for surgery was not seen in patients who received GK as part of their treatment. Survival of patients by primary site was 6, 9.5 and 7 months for NSCLC, breast and colorectal cancers respectively. Patients with resected primary tumors had a median survival of 9 months compared with 5.5 months for those whose primary tumors were treated with radiation ± chemotherapy respectively. Conclusions: Local control of treated metastatic lesions is superior with the radiosurgery arms. However, the risk of developing new brain lesions is higher for patients not receiving whole brain radiotherapy. There was no difference in overall survival between the three arms. Resection of metastatic lesions did add to overall survival, but not for those receiving radiosurgery. Patients with breast and colorectal cancer faired better than those with lung cancer. Survival was better for patients with resected primary tumors compared to those treated with radiation ± chemotherapy. Editor's note: Both randomized trials did not show a survival advantage to radiosurgery either alone or added to whole brain radiotherapy for patients with multiple brain metastases. The RTOG results presented are the group of patients randomized who had 2-3 brain metastases, a separate group of patients with solitary brain metastases is still being accrued as part of this trial. The Rhode Island trial included patients with solitary brain metastases and also allowed patients to be randomized between the three arms. Not surprisingly, there was no survival benefit noted with radiosurgery boost in either trial and this was attributed to the progression of the underlying systemic malignancy as the primary determinant of survival in patients with brain metastases. With regards to local control, the results of the RI study are difficult to interpret because of the failure to stratify according to the use of surgery between the three arms. In the RTOG study, a trend was demonstrated towards improved local control with radiosurgery (21% vs 35% local relapse, SRS vs no SRS, p=0.1) The lack of a statistical significance in local control may be a consequence of patient numbers or the multi-institutional nature of the study. Also, the local control with whole brain radiotherapy alone was somewhat better than one might expect from historical data. The theme of radiosurgery in brain metastases was continued in a panel debate between Drs Shaw, Regine, Patchell and Kondziolka. Two questions were posed: What is the role of WBXRT added to surgery or radiosurgery for patients with solitary metastases? What is the role of radiosurgery for patients with multiple brain metastases? Dr. Regine, in addressing the first question concentrated mainly on the University of Kentucky data that demonstrated a significant decrease in the incidence of "in brain" relapse with WBXRT added to surgery vs. surgery alone (18% vs 70%) and noted a shift in the pattern of patient deaths from deaths due to intracranial disease to deaths due to extracranial disease in patients receiving WBXRT. Dr. Shaw concentrated on autopsy data that suggested as many as 50% of patients with brain metastases have truly solitary metastases and focussed on the lack of an overall survival advantage to whole brain radiotherapy and the potential neuro-toxicity. He proposed that wide field local radiation or a radiosurgery boost be considered post surgery for patients with solitary metastases. The audience remain unconvinced however and voted in favour of WBXRT + Sx both before and after the debate when presented with a case study of a patient with a solitary brain metastases from lung cancer with stable systemic extracranial disease. Dr. Kondziolka, in addressing the second question, quoted the University of Pittsburgh randomized trial demonstrating a survival advantage and improved local control to radiosurgery boost in patients with multiple brain metastases compared to WBXRT. Dr. Patchell, in a plea for evidence based treatment decisions, discussed methodologic problems with the existing randomized trials of radiosurgery in patients with multiple brain metastases and pointed to the RTOG 9508 results (demonstrating no advantage to radiosurgery boost) as the most robust data set available to date. At the end of the debate, a substantial number of audience participants changed their stance from "would treat with radiosurgery " to "would not" when presented with a case of a patient with 2 brain metastases and stable extracranial disease. Finally, the current RTOG brain mets trial for 1-3 mets comparing radiosurgery alone vs. WBXRT +radiosurgery was discussed. Theme II: Novel systemic agents combined with WBXRT for patients with brain metastases A Phase II Randomized Trial of Synchronous Radiotherapy with Temozolomide in Brain Metastases E. Paraskevaidis, D. Antonadou , G. Sarris, N. Kolliarakis, I. Economou, P. Karageirgus and N. Throuvalas Metaxas Cancer Hospital, Pireus, Greece Purpose: Radiation treatment is the most effective treatment for brain metastases, but the duration of response is limited. Temozolomide (TMZ) is an oral cytotoxic agent which crosses the brain barrier. In this phase II controlled clinical trial we evaluated the efficacy and safety of synchronous administration of TMZ and XRT in patients with brain metastases. Materials and Methods: Eligibility included adults (age>18) with confirmed brain metastases with CT scan or MRI, with PS<2. Patients underwent conventional XRT with a daily fraction of 2Gy daily/ 5 days per week to a total dose of 40Gy and were randomized to receive daily TMZ 75mg/m2 during XRT (TMZ+XRT arm), or XRT alone (control arm). In theTMZ+XRT arm, TMZ was also administered at a dose of 200 mg/m2 for 5 consecutive days one month post XRT. This cycle was repeated monthly for 6 months. The primary study endpoint was response to treatment. Results: 28 patients were entered in this trial. 15 patients in the TMZ + XRT arm and 13 in the control arm. Two months post XRT patients were evaluated for response with neurological examination and CT scan. Major neurological symptoms were not present in 12 patients in TMZ + XRT arm versus 7 patients in the control arm (p=0.05). The CT assessment showed 7 complete and 3 partial responses in the TMZ + XRT arm versus 2 complete and 5 partial responses in the control arm (CR:p=0.038, PR:p=0.410). Responses were independent of the primary tumour site. TMZ administration was well tolerated. Updated survival and pattern of failure data will be presented. Conclusion: Combined treatment with XRT and TMZ produces significant response rates in this patient population. RSR13 Plus Cranial Radiation Therapy Improves Survival in Patients with Brain Metastases Compared to the RTOG Recursive Partitioning Analysis Brain Metastases Database: Update of a Phase II Trial E. Shaw1, C. Scott2, B. Stea3, J. Suh4, S. Kadish5, J. Hackman6, A. Pearlman1, M. Gerber6, K. Murray2, L. Gaspar2, M. Mehta2 and W. Curran2. 1Wake Forest University School of Medicine, Winston-Salem, NC 2Radiation Therapy Oncology Group, Philadelphia, PA 3University of Arizona Health Sciences Center, Tuscon, AZ 4Cleveland Clinic Foundation, Cleveland, OH 5St. Vincent Hospital, Worcester, MA and 6Allos Therapeutics, Denver, CO RSR13 is a potential enhancer of ionizing radiation by decreasing hemoglobin-O2 binding affinity and increasing tumor oxygenation. This Phase II open-label multi-center study assessed the efficacy/safety of RSR13 plus external beam cranial radiation therapy (RT) in patients (pts) with brain metastases. The primary endpoint was survival compared to the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). Cause of death and response were also assessed. Materials and Methods: Eligibility: Age >=18, KPS >=70, histologies including non-small cell lung, breast, melanoma, GU, or GI cancer (CA). Pts received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 75-100 mg/kg IV over 30 minutes via central venous catheter. Uni- and multi-variate comparisons were made between study pts and 1070 RTOG RPA Class II BMD pts for survival and cause of death. Results: Per study design, 57 RPA Class II pts were enrolled. Characteristics were: 75% age <=65; 54% female; 61% KPS 90-100; 58% lung CA, 32% breast CA, 5% GU CA, 5% melanoma; 67% uncontrolled primary; 74% extracranial metastases. 80% pts completed >=90% RSR13 doses, 88% pts completed >=70% RSR13 doses, and 14% pts terminated study during dosing. 32% had a treatment related >=Grade 3 toxicity including: headache, altered mental status, nausea/vomiting, hypoxemia, allergic reaction, and/or transient renal dysfunction. With follow-up of 10.3-22 months (mos) for the 11 pts who are still alive, pts treated with RSR13 had a median survival time (MST) of 6.4 mos vs 4.1 mos for the RPA BMD control group (p=0.0165). Survival rates at 6 mos and 1 year were 51% and 22% with RSR13 vs 35% and 15% for the RPA BMD control group. In an exact case-matched analysis (n=38), MST was 7.3 mos with RSR13 vs 3.4 mos for the RPA BMD control group (p=0.0036), and survival rates at 6 mos and 1 year were 58% and 23% with RSR13 vs 21% and 8% for the RPA BMD. Death due to brain metastases occurred in 11% of RSR13 treated pts vs 37% of pts in the RPA BMD (p=0.0003). In a Cox model multivariate analysis, RSR13 treated pts had a 58% reduction in risk of death (p=0.0168) vs exact case-matched controls. Assessment of imaging based response was complete in 12% and partial in 25%. The median survival time was 13.7 mos in complete responders, 8.4 mos in partial responders, and 5.2 mos in those with stable or progressive disease. Conclusions: RSR13 plus cranial RT resulted in a significant improvement in survival as well as a reduction in death due to brain metastases compared to the RTOG RPA Class II BMD. A Phase III randomized trial of cranial RT with or without RSR13 is ongoing. Xcytrin*(Motexafin Gadolinium) and Whole Brain Radiation for Patients with Brain Metastases: Lead-In Phase to Randomized Trial - Final Result M. P. Mehta1, C. A. Meyers2, W. J. Curran3, C. J. Schultz 4, J. M. Ford5, W. H. Roa 6, M. Leibenhaut 7, A. J. Cmelak 8, A. Rao 9, R. D. Timmerman 10, L. Gaspar 11, S. C. Phan 12, D. Eber 12 and M. F. Renschler12 1University of Wisconsin, Madison, WI 2University of Texas MD Anderson Cancer Center, Houston, TX 3Thomas Jefferson University, Philadelphia, PA 4Medical College of Wisonsin, Milwaukee, WI 5UCLA, Los Angeles, CA 6Cross Cancer Institute, Edmonton, AB, Canada, 7Radiological Associates of Sacramento, Sacramento, CA 8Vanderbilt University, Nashville, TN 9Kaiser Permanente, Los Angeles, CA 10Indiana University, Indianapolis, IN 11University of Colorado, Denver, CO and 12Pharmacyclics, Sunnyvale, CA Purpose: To evaluate 1 novel MRI, neuro-cognitive and quality of life endpoints in preparation of their use in a prospective, randomized Phase III trial and 2. to obtain additional safety and efficacy data in 25 patients when the radiation enhancer XCYTRIN*(motexafin gadolinium, also known as gadolinium texaphyrin) is administered with whole brain radiation therapy (WBRT). Materials & Methods: In a prospective, multi-center, international trial, patients with brain metastases were treated with XCYTRIN (5 mg/kg/d IV) prior to each of ten 3Gy fractions of WBRT. Patients with unresected and previously unirradiated brain metastases and KPS>70 were eligible. Patients were evaluated by MRI, FACT-BR, and a battery of neuro-cognitive tests (Trail Making A&B, Grooved Pegboard Test, Hopkins Verbal Learning Test, Controlled Oral Word Association Test) before WBRT and at regularly scheduled follow-up time points. Results: 25 patients with a median age of 56 years (range 33-78) and brain metastases from lung (52%) and breast (24%) cancer, RPA class 2 (96%) with uncontrolled primaries (56%) and extracranial sites of metastasis (84%) were enrolled. Patients had an average of 12 brain metastases (range 1-51), and 76% were radiosurgery ineligible by RTOG criteria. Follow-up is mature, with a minimum follow-up of survivors (16%) of 1 year. Overall, XCYTRIN was well tolerated. Median survival (MS) was 5.0 months. Cause of death was systemic cancer progression or cancer complications (71%), CNS progression (19%) or unknown (10%). Radiologic response rate by MRI in 19 patients with at least one evaluable follow-up scan was 68% (CR 5%, PR 63%, SD 16%, PD 16%). All responses occurred within 2 months of treatment. Median time to radiologic progression (censored for death) was 8.9 months. Tumor selectivity of XCYTRIN was established using MRI, which showed selective drug uptake and accumulation in the metastases but not in normal brain. Administration of the battery of neuro-cognitive tests was found to be feasible in all patients, with each testing session lasting 20 to 40 minutes. Significant impairment in neurocognitive function (NF) was noted at presentation with an average of 3.5 of 8 test performed scoring in the impaired range (15 SD below normative mean). The number of impaired tests at presentation predicted for poorer survival, ranging from 0 impaired tests (MS 10 months) to 7 impaired tests (MS 17 months). Following WBRT and XCYTRIN therapy, 45% of patients had a significant overall improvement in NF. Improvement in NF at 1 month, seen in 9 of 20 evaluable patients, was associated with a MS of 9.5 mo compared to 5.1 mo in patients with a decline. There was no evidence of late deterioration in neurocognitive function. Conclusion: 1 In patients with brain metastases, XCYTRIN was well tolerated when administered daily with WBRT. 2. Local control was achieved and maintained in the majority of patients. 3. The degree of neurocognitive impairment at presentation correlated with poor survival. 5. Improvement in neurocognitive function one month after treatment correlated with improved survival. Based on this experience, the definitive randomized Phase III trial has been initiated. Editor's note Encouraging results were presented for patients with brain metastases treated with novel agents: temozolamide (an oral nitrosourea like agent that penetrates the brain), RSR13 (an oxygen "unloader" to improve tissue oxygenation) and motexafin gadolinium (an agent that acts by potentiating free radical damage by altering the redox status of cancer cells). All 3 agents produced improvements in median survivals from 3-5 months to 7-9months (compared to WBXRT historical controls) and are the subject of larger phase III trials. It is also worth noting that all 3 agents will be examined in a phase III manner for patients with glioblastoma multiforme as well. Theme 3: Biologic imaging MR-Spectroscopy Results in Improved Target Delineation for High-Grade Gliomas A. Pirzkall1,2, D. A. Larson1, T. R. McKnight1, E. E. Graves1, S. J. Nelson1 and L. J. Verhey1 1University of California San Francisco, San Francisco, and 2University of Heidelberg & German Cancer Research Center, Heidelberg, Germany Purpose: IMRT is a powerful approach to delivering a highly conformal, escalated dose to MRI defined growth regions (T1) of malignant brain tumors while delivering a lower dose to defined microscopic disease (T2) (integrated boost irradiation). However, functional / metabolic information provided by MR-spectroscopy (MRS) suggests microscopic tumor extension and active tumor growth in regions that do not correspond to MRI data alone. A study was undertaken to assess the impact MRS might have on the target volume used for IMRT treatment planning for high-grade gliomas. Materials and Methods: Thirty patients (20 astrocytomas WHO III, 10 WHO IV (GBM)) were evaluated, each of whom had undergone MRI and MRS studies prior to surgery. For each patient, the MRI data set was manually contoured; regions of interest included the T1 region of contrast enhancement (T1) and the T2 region of hyperintensity (T2). The 3D-MRS peak parameters for choline (Cho) and N-acetyl-aspartate (NAA), acquired on a voxel-by-voxel basis, were categorized based on an Abnormality Index (AI), a newly developed tool for quantitative assessment of tissue metabolite levels. An AI of 2 was defined as the lowest value corresponding to biopsy confirmed tumor. The AI data were aligned to the MRI and displayed as 3D contours. T1 is classically considered to be the region of active disease, T2 the region of microscopic and / or suspected disease, and AI can be viewed as a continuous measure of disease activity (higher being more metabolically active). The conjoint and disjoint volumes for the following contours were defined: T1 vs. AI 2-6; T2 vs. AI 2. These were then compared with those based on MRI alone. Results: There was substantial variation in the relationship between the MRI and MRS designated volumes. The data suggest that for both grades III and IV, the T2 volume as region at risk of microscopic disease was overestimated: the AI 2 volume was less than the T2 volume in 80-90 % of patients; on average, 9 and 10 cc of AI 2 were not in the T2 volume (gr. III and IV) whereas 27 and 44 cc of T2 were not in the AI 2 volume. The area of T1 as active disease was underestimated: the AI 3 and 4 volumes exceeded the T1 volume in 90-100 % of patients; on average, 15 / 27 cc (gr. III) and 11 / 17 cc (gr. IV) of AI 3 / 4 were outside of the T1 volume; however, in 35-80 % average T1 volumes of 3.2 cc up to 16 cc were not circumscribed by the AI 3 / 4 volume. Conclusion: Traditional MRI tends to underestimate the region of active growing tumor and overestimate the region at risk of microscopic disease as compared to MRS. The use of MRS to define target volumes for IMRT treatment planning for subtotally resected / biopsied / recurrent high-grade gliomas would change the volume receiving a boost dose and significantly reduce the volume receiving a standard dose. This may improve control while reducing complications. Somatostatin Receptor Scintigraphy (OCTREOTIDE®) Imaging: An Assessment of Meningioma Response Following Radiation Therapy R. S. Hudes, D. W. Andrews, S. K. Kim, C. M. Intenzo, M. Werner-Wasik, B. W. Corn and W. J. Curran Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA Background: Patients with meningioma treated with radiation therapy are followed with anatomic imaging with the criteria for success being absence of tumor progression. Indium-111 labeled somatostatin scintigraphy (octreotide brain SPECT) is useful in the diagnostic evaluation of patients with meningioma (Hildebrandt, Acta Neurochir 126:63-71; 1994). Octreotide brain SPECT was evaluated as a functional imaging modality to assess response to radiation therapy among patients with meningioma. Materials & Methods:: Between December 1995 and May 1998, 44 patients were treated for meningioma with radiation therapy at Thomas Jefferson University Hospital and Wills Eye Hospital. Octreotide brain SPECT was performed on 39 patients prior to radiation therapy. Thirty patients were followed after radiation therapy (RT) with at least one octreotide imaging study, in addition to magnetic resonance imaging (MRI) or computed tomography (CT). Radiation therapy techniques included conformal radiotherapy (6 patients), fractionated stereotactic radiotherapy (21 patients) and stereotactic radiosurgery (3 patients) with median doses of 54.0 Gy, 54.0 Gy and 15.0 Gy, respectively. Results: A total of 103 octreotide brain SPECT studies among the thirty patients were reviewed. All thirty patients had increased uptake of radiotracer on baseline octreotide imaging studies prior to radiation therapy. The median interval to obtaining the first post-RT octreotide and MRI/CT studies was 3.6 months (0.5-7.5 months). In that time period, no responses were documented on MRI or CT scan. In contrast, 24 patients (80%) had decreased uptake of the radiotracer compared to the baseline study, 5 patients had stable uptake and 1 patient had increased uptake. The median change in radiotracer uptake was a decrease of 25% (-100% to +9%) on the first post-RT study. By the last follow-up study at a median interval of 14.9 months (2.4-40.5 months), 27 patients (90%) had demonstrated decreased uptake without subsequent interval increased uptake. Two patients had increase uptake at 2.4 and 30.8 months. Both of these patients with increased uptake had malignant meningiomas and clinical and MRI evidence of tumor progression. Conclusion: Octreotide brain SPECT provides functional imaging evidence of response to radiation therapy in patients with meningioma. In contrast to MRI/CT imaging, the response demonstrated on octreotide brain SPECT is quantifiable and may be complementary to the follow-up evaluation of meningioma patients treated with radiation therapy. Editor's note The study from UCSF demonstrated that use of metabolic signatures to identify potential areas of tumor activity did correlate 100% with the typical T2 and T1 enhanced volumes that are used form radiation treatment planning. Biopsy correlation of the metabolically abnormal areas are being carried out to identify the significance of the abnormal metabolic signatures. If the gradient of tumor, histologically, is mapped to the areas of metabolic changes in activity then radiation therapy (either conventional dose or dose escalation) to the metabolically abnormal areas becomes a very feasible treatment strategy. Such directed therapy may be a way to feasibly escalate the dose and these finds may also explain why dose escalated therapy to the T1 enhanced volume (by radiosurgery, brachytherapy or 3D/IMRT) has still been associated with substantial rates of local failure. The paper from Hudes et al presented a different form of metabolic imaging based on the finding that meningiomas express somatostatin receptors. Decreases in uptake of radiolabelled octreotide was noted post radiation. As of yet, the author's have not tried therapeutic doses of radiolabelled octreotide to treat meningiomas (as has been used in neuroendocrine tumors like carcinoid) but this may be a future strategy, especially for patients with multiple meningiomas or meningiomas recurrent post external beam radiotherapy. ****************** Radiobiology: Withers 11/00 No Reference Selected ****************** Health Services Research: Hayman 11/00 AU: Potosky AL, Legler J, Albertsen PC, Stanford JL, Gilliland FD, Hamilton AS, Eley JW, Stephenson RA, Harlan LC. TI: Health Outcomes After Prostatectomy or Radiotherapy for Prostate Cancer: Results From the Prostate Cancer Outcomes Study. SO: J Natl Cancer Inst. 2000 Oct 4;92(19):1582-1592. URL: http://jnci.oupjournals.org/cgi/content/full/92/19/1582 ID: PMID: 11018094 UI: No Cit. ID assigned Abstract: BACKGROUND: Radical prostatectomy and external beam radiotherapy are the two major therapeutic options for treating clinically localized prostate cancer. Because survival is often favorable regardless of therapy, treatment decisions may depend on other therapy-specific health outcomes. In this study, we compared the effects of two treatments on urinary, bowel, and sexual functions and on general health-related quality-of-life outcomes over a 2-year period following initial treatment. METHODS: A diverse cohort of patients aged 55-74 years who were newly diagnosed with clinically localized prostate cancer and received either radical prostatectomy (n = 1156) or external beam radiotherapy (n = 435) were included in this study. A propensity score was used to balance the two treatment groups because they differed in some baseline characteristics. This score was used in multivariable cross-sectional and longitudinal regression analyses comparing the treatment groups. All statistical tests were two-sided. RESULTS: Almost 2 years after treatment, men receiving radical prostatectomy were more likely than men receiving radiotherapy to be incontinent (9.6% versus 3.5%; P:<.001) and to have higher rates of impotence (79.6% versus 61.5%; P:<.001), although large, statistically significant declines in sexual function were observed in both treatment groups. In contrast, men receiving radiotherapy reported greater declines in bowel function than did men receiving radical prostatectomy. All of these differences remained after adjustments for propensity score. The treatment groups were similar in terms of general health-related quality of life. CONCLUSIONS: There are important differences in urinary, bowel, and sexual functions over 2 years after different treatments for clinically localized prostate cancer. In contrast to previous reports, these outcome differences reflect treatment delivered to a heterogeneous group of patients in diverse health care settings. These results provide comprehensive and representative information about long-term treatment complications to help guide and inform patients and clinicians about prostate cancer treatment decisions. Editor's comments: The key issue here is the ability to generalize. As you may know, almost all of the studies of patient-reported quality of life following treatment with either surgery or radical prostatectomy have come from large academic centers. Because these are tertiary care facilities, most of us would probably agree that the patients seeking care at these institutions may not be representative of the typical patient with early-stage prostate cancer. Although I do not want to get drawn into the "town vs. gown" controversy, one could also imagine differences in outcomes based where the treatment is delivered too (not every urologist is Patrick Walsh!). The strength of this manuscript is the fact that the authors used a subset of the SEER registries to identify a cohort of patients with early stage prostate cancer treated with either surgery or external beam radiation therapy between 10/94-10/95 soon after diagnosis. Because the SEER registries are population-based, the groups of patients undergoing surgery and RT should be more representative of the average patient receiving this treatment than a convenience sample drawn from a single academic center. Not surprisingly, the patients who received radiation were older, had higher PSAs, had worse pre-treatment urinary, bowel and sexual functioning and had more comorbid illnesses. After adjusting for these differences, the results were as noted above in the abstract. There are several points that are worth emphasizing. First, at least in my experience, the risks of incontinence, bowel dysfunction and impotence associated with radiation are pretty similar those commonly quoted by radiation oncologists (see Fowler JAMA 2000;283:3217-22) while those associated with surgery are higher. Secondly, while bowel function was worse in the RT patients at two years, the degree of bother due to bowel dysfunction was the same in the RT and RP patients, suggesting that most patients treated with RT who experience bowel dysfunction adapt to their difficulties with time. In contrast, a greater percentage of the patients who undergo RP who experience urinary and sexual dysfunction continue to appear to be bothered by these symptoms. As detailed by the authors in the discussion, this study has a number of limitations. Potential problems include recall bias (they asked patients to recall their baseline functioning 4-6 months after diagnosis), low response rate (only 62% of subjects approached agreed to participate in the baseline survey, which actually isn't that bad, and the non-responders could differ from the responders in important ways), loss to follow-up (not everyone continued to fill out the survey at 12 and 24 months and, again, these non-responders could be different from the responders in important ways) and unobserved confounders (while they corrected for all known differences between the two groups there may be other unknown factors). Despite these limitations, in my opinion, this is the best information currently available regarding the risks of urinary, bowel and sexual dysfunction following RP and RT for the average patient with early stage prostate cancer. For those of you who are interested in learning more about PCOS, Arnie Potosky has agreed to give a talk about the study at the Outcomes Meeting being sponsored by ASTRO on June 2, 2001 in Toronto. ****************** Radiation Biophysics: Chen 11/00 No Reference Selected ****************** Brian J. Goldsmith, M.D. Moderator, IROJC