From owner-radoncjc@net.bio.net Mon Jul 24 16:48:33 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 4C72817B02; Mon, 24 Jul 2000 16:48:29 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 2FE1E17AFD; Mon, 24 Jul 2000 16:48:27 +0100 (BST) To: radoncjc@net.bio.net From: Goldsmithb@radiological.com Reply-To: radoncjc@net.bio.net Date: 7/6/00 9:04AM Subject: July 2000 Internet Radiation Oncology Journal Club (IROJC) Message-Id: <20000724154827.2FE1E17AFD@mercury.hgmp.mrc.ac.uk> Sender: owner-radoncjc@net.bio.net Precedence: bulk July 2000 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 62nd 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. Ph.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. Comments should be in compliance with IROJC commentary rules (see below). In the month that follows this posting of references, submitted comments will be delivered to the e-mail boxes of the IROJC readership. ------------------------------------------------------------ ARCHIVED IROJC material is available at http://www.bio.net/hypermail/radoncjc/ ------------------------------------------------------------ Commentary Rules: (1) Please cite the subject category in the header of your e-mail message, e.g., Subject: CNS 7/00. (2) Address the readership at large - not the Editor who suggested the reference. The Editor is under no obligation to respond to questions posed by the IROJC readership. (3) The Editor's selection is not necessarily an endorsement of the authors' conclusions. In fact, articles may be selected for criticism. (4) Comments posted to the Internet are public. Professional wording is prudent. (5) Comment only on journal articles that you have read recently, and please keep comments specific. (6) In order to minimize confusion, limit comments to the current month's list of references. (7) Please sign all comments and questions to the IROJC. By identifying yourself, you promote a more collegial and friendly environment! (8) Address to the Moderator (goldsmithb@radiological.com) private questions and comments which are not intended for IROJC posting and public reading. ****************** Peds: Donaldson 7/00 AU: Wolden SL; Steinherz PG; Kraus DH; Zelefsky MJ; Pfister DG; Wollner N. TI: Improved long-term survival with combined modality therapy for pediatric nasopharynx cancer. SO: Int J Radiat Oncol Biol Phys 2000 Mar 1;46(4):859-64. Abstract: PURPOSE: Nasopharynx cancer is a rare malignancy in childhood. This study aims to determine the role of chemotherapy, the optimal dose of radiation, and the long-term outcome for children with locoregional disease. METHODS AND MATERIALS: Thirty-three patients [median age 14 (range: 12-20) years] were treated for Stage I-IVB nasopharynx cancer. Thirteen patients (39%) received radiotherapy alone and 20 patients (61%) had chemotherapy and radiotherapy. The median radiation dose to the primary tumor was 66 Gy (range: 54-72 Gy). The median follow-up time for surviving patients was 8.4 years (range: 0.5-23.6 years). RESUL TS: The actuarial 10-year locoregional relapse-free survival, distant metastases-free survival, and overall survival rates were 77%, 68%, and 58% , respectively. Locoregional control was improved for patients treated with radiation doses > 60 Gy compared to those receiving < or = 60 Gy (93% vs. 60%, p < 0.03). The addition of chemotherapy had no significant effect on locoregional control but did reduce the development of distant metastases (16% vs. 57%, p = 0.01). Combined modality therapy improved 10-year disease-free survival (84% vs. 35%, p < 0.01) and survival (78% vs. 33%, p < 0.05) over radiation alone. The 10-year actuarial rate of severe complications was 24%.60 Gy are used for gross disease. The addition of chemotherapy decreases the risk of distant metastases and increases survival. Editor's comments: Combined modality therapy has now become the standard of care for children with nasopharyngeal carcinoma, as confirmed by this well analyzed and well written retrospective review from MSKCC. Whereas in many pediatric cancers treated with chemo-radiotherapy, there may be pressure to reduce radiation doses to "avoid late effects of radiotherapy", Wolden et al. clarify that one must not reduce the radiation dose to the primary nasopharynx tumor, even in the setting of chemotherapy. To do so will risk local recurrence. The value of chemotherapy in this disease is to reduce distant relapse. Radiation dose to the nasopharynx must not be lowered below 60 Gy, and most would use 3D-CRT and/or IMRT to boost the dose higher. This is an important paper to reference when you see a child with primary nasopharynx cancer. ****************** Head/Neck/Skin: Foote 7/00 AU: Lee WY; Hsiao JR; Jin YT; Tsai ST. TI: Epstein-barr virus detection in neck metastases by in-situ hybridization in fine-needle aspiration cytologic studies: An aid for differentiating the primary site SO: Head Neck 2000 Jul;22(4):336-40. Abstract: BACKGROUND: Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV). The metastasis to cervical lymph nodes represents a frequent initial manifestation of NPC. The usefulness of EBV detection by polymerase chain reaction (PCR) in the diagnosis of occult NPC with cervical metastasis has been reported. Our previous study showed that EBER1 in-situ hybridization was somewhat more sensitive and specific than PCR in detecting EBV in the evaluation of specimens from a population at high risk for NPC. METHODS: Fine-needle aspiration cytologic specimens of neck masses from 30 patients were investigated, including 10 NPC primary tumors, 19 squamous cell carcinomas from other sites of the head and neck (9 oral cavity, 2 paranasal sinuses, 2 oropharynx, 3 larynx, and 3 hypopharynx), and 1 diffuse large-cell lymphoma. EBER1 in-situ hybridization was performed on direct smears made from aspirates. RESULTS: EBER1 signals were detected in all neck metastases from the nasopharynx but none of the specimens from other primary sites. CONCLUSIONS: This study suggests that EBER1 in-situ hybridization can be used as a supplemental tool for differential diagnosis whenever fine-needle aspiration cytologic examination is presented with a neck metastasis without knowing the primary site. Copyright 2000 John Wiley & Sons, Inc. Head Neck 22: 336-340, 2000. Editor's comments: This study suggests that EBER 1 in-situ hybridization can be used to direct the clinical exam, primary tumor site biopsy and radiation therapy treatment field design in patients presenting with malignant cervical adenopathy from an occult primary. ****************** GYN: Petereit 7/00 AU: Chi DS; Venkatraman ES; Masson V; Hoskins WJ. TI: The ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in stage III epithelial ovarian carcinoma. SO: Gynecol Oncol 2000 May;77(2):227-31. Abstract: PURPOSE: The aim of this study was to determine the ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in patients with Stage III epithelial ovarian carcinoma. METHODS: We performed a retrospective chart review of 100 consecutive patients with Stage III ovarian carcinoma who had a serum CA-125 drawn prior to primary cytoreductive surgery. We used a receiver operating characteristic curve to determine the CA-125 level with the maximal prognostic power in predicting optimal versus suboptimal cytoreduction. RESULTS: The median CA-125 level for the 100 patients was 819 U/ml (range 5.6-26,200 U/ml). Optimal cytoreduction (diameter of largest residual tumor nodule < or =1 cm) was obtained in 45 cases (45%). The probability of performing optimal cytoreduction decreased with increasing CA-125 levels. A preoperative CA-125 level of 500 U/ml was identified as the value with the most predictive power. Optimal cytoreduction was achieved in 33 of the 45 cases (73%) with a CA-125 less than 500 U/ml compared to only 12 of the 55 cases (22%) with a CA-125 greater than 500 U/ml. Using a threshold level of 500 U/ml, the preoperative serum CA-125 level was able to predict optimal versus suboptimal cytoreduction with a sensitivity of 78%, specificity of 73%, positive predictive value of 78%, and negative predictive value of 73%. CONCLUSION: The probability of performing optimal cytoreduction in patients with Stage III ovarian carcinoma and a preoperative CA-125 greater than 500 U/ml was approximately one in five. These patients may be candidates for initial laparoscopic evaluation to obtain a confirmatory tissue diagnosis and to determine resectability. Copyright 2000 Academic Press. Editor's comments: The gynecologic group from MSKCCC published a provocative paper that attempted to identify advanced ovarian cancer patients who had a lower chance of being optimally debulked using preoperative CA-125 levels. About 75% of patients with CA-125 levels < 500 U/ml were optimally debulked whereas approximately 20% were cytoreduced with CA-125 levels > 500 U/ml. The definition of optimally cytoreduction continues to change. The value was changed from 3 cm to 2 cm, to presently 1 cm-per the GOG definition. The formal definition means that each individual tumor mass is resected to a volume < 1 cm. This level of debulking is determined somewhat subjectively by the operating gynecologic oncologist. The point that continues to be debated is whether optimal cytoreduction is a result of a very talented surgeon, or is it determined by both the talent of the surgeon and biology of the disease? Most "seasoned" gynecologic oncologists will achieve a similar amount of debulking. What biologic factors might predict for unresectability ? Some known unresectable features include intraparenchymal liver metastases, porta hepatis involvement and bulky diaphragmatic disease to name a few. The authors postulate that a reliable biologic marker for resectability might be the CA-125 level. The CA-125 level for resectability was 500 U/ml: 73% vs 22% optimally debulked. The authors contend that patients who have a CA-125 level exceeding 500 U/ml might be offered an alternative strategy in which they would be assessed laparoscopically to determine resectability. If they were deemed to be unresectable ("peek and schriek!"), then neoadjuvant chemotherapy for 3 to 6 cycles would be delivered before commencing with a definitive operation. Promising results have been reported using the neoadjuvant approach in selected patients. Berek reviews their article and points out that laparoscopic assessment may not truly identify resectable patients and therefore women with CA-125 levels > 500 U/ml may be denied a potentially curative approach. This paper does add credibility to investigating alternative treatment approaches in women who ultimately may have disease that is not amenable to optimal debulking upfront. ****************** GI / Soft Tissue Sarcoma: Tepper 7/00 AU: Macdonald JS, Smalley S, Benedetti J, Estes N, Haller DG, Ajani JA, Gunderson LL, Jessup MM, Martenson JA. TI: Postoperative combined radiation and chemotherapy improves disease-free survival (DFS) and overall survival (OS) in resected adenocarcinoma of the stomach and G.E. junction. Results of Intergroup Study INT-0116 (SWOG 9008). SO: Proc ASCO, page 1a, 2000 URL: http://www.asco.org/prof/me/html/00abstracts/p/m_1.htm Abstract: The cure rate for patients with resected gastric cancer is 5% - 40%. INT-0116 was designed to evaluate post-operative adjuvant chemoradiation in resected gastric cancer. STUDY DESIGN: Patients with stages Ib through IV M0 adenocarcinoma of the stomach or gastroesophageal junction who had undergone gastric resection with curative intent were randomized to postoperative follow up or chemoradiation. The treatment consisted of one cycle of 5-FU (425 mg/m@)/Leucovorin (LV) (20 mg/m@) in a daily x5 regimen followed by 4,500 cGy (180 cGy/day) given with 5-FU/LV (400 mg/m@ and 20 mg/m@) on days 1 through 4, and on the last 3 days of radiation. One month after completion of radiation, two cycles of daily x5 5-FU/LV (425 mg/m@ and 20 mg/m@) were given at monthly intervals. RESULTS: Between 8/1/91 and 7/15/98, 603 patients were accrued to this study, 47 (8%) of which were ineligible. There were no significant differences between treatment and observation groups in regard to age, sex, race, T or N stage. Nodal metastases were present in 85% of cases. The combined modality regimen in this program was tolerable. There were 3 (1%) toxic deaths. Grade 3 and grade 4 toxicity occurred in 41% and 32% of cases, respectively. The > or = gr. 3 toxicity frequencies were: hematologic (54%), GI (33%), infection (6%), neurologic (4%). OS and DFS analyses were based on intention to treat. With 3.3 years of median follow up, 3-year DFS is 49% for treatment and 32% for observation (p=.001); 3-year OS is 52% for treatment and 41% for observation (p=.03). P values are 2-sided. These results demonstrate a 44% improvement in relapse-free survival (hazard ratio of 1.44), and a 28% improvement in survival with median survival of 27 months in the observation arm vs. 42 months in the treatment arm (hazard ratio 1.28). Postoperative chemoradiation may now be considered a standard of care for high-risk R0 resected locally advanced adenocarcinoma of the stomach and GE junction. Supported in part by NCI grants: 5U10 CA32102, U10 CA31946, U10 CA15488, U10 CA25224, U10 CA21661. Editor's comments: I have avoided putting abstracts in the journal club since they are by their nature somewhat preliminary. However, this article is so important that I could not avoid including it. I will also likely include it again when the final publication comes out. For many years there has been minimal use of radiation therapy in gastric cancer. The few studies that have evaluated radiation therapy alone have not shown a survival advantage although they have shown an advantage in local control. There is minimal information in the literature on combined chemoradiation therapy in this disease. The present study was initiated 9 years ago to test the combination in the postoperative setting. The chemotherapy that was used was not optimized, but it was used since this was a regimen that had been through toxicity studies. The results were viewed by many as surprising and truly will change standards of care. There was a major survival advantage to the use of combined modality therapy postoperatively which was highly statistically significant. Although the data was not presented in the abstract, it is important to be aware that the improvement was entirely due to an improvement in local control. There was no improvement in distant mets. This strongly suggests that this is another disease site, along with a growing number, where there is good data that chemotherapy is making an impact by its ability to assist radiation therapy in obtaining local control. Lest people think that the positive results were due to treatment of GE junction tumors, only about 20% of tumors were cardiac in origin. The troubling part of this study is the fact that without an extraordinary effort in RT quality control on the part of Steve Smalley, that this study would likely have been a bust. Many patients before RT review had fields which were either inadequate for covering the high risk volume or were so large that majority morbidity would likely have resulted. I think this is due to the fact that very few radiation oncologists have been trained in how to treat gastric cancer and understand the patterns of spread. In order to help correct this, there will a special session at ASTRO this year to review RT parameters for gastric cancer and an article is being written by Steve Smalley, with help from Len Gunderson and me and others, for publication in the red journal. Hopefully these educational efforts will assist the rad onc community. In the meantime, knowing the patterns of tumor spread based on the location of the primary tumor mass and extent as defined in the textbooks (see deVita for example) should assist in treatment planning. Also, it needs to be realized that the fields defined in the previous protocol will at times (maybe often) be too large to treat safely, and need to be modified based on patterns of spread and estimates of toxicity. There will undoubtedly be substantial modifications of what we deem to be the "proper" fields as we learn more about this disease and the role of RT. This is a seminal study. Steve Smalley should be congratulated for his enormous efforts. Further information will come later. ****************** CNS: Bauman 7/00 AU: Ling CC, Humm J, Larson S, Amols H, Fuks Z, Leibel S, Koutcher JA. TI: Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. SO: Int J Radiat Oncol Biol Phys. 2000 Jun 1;47(3):551-60. Abstract: Purpose: The goals of this study were to survey and summarize the advances in imaging that have potential applications in radiation oncology, and to explore the concept of integrating physical and biological conformality in multidimensional conformal radiotherapy (MD-CRT).Methods and Materials: The advances in three-dimensional conformal radiotherapy (3D-CRT) have greatly improved the physical conformality of treatment planning and delivery. The development of intensity-modulated radiotherapy (IMRT) has provided the "dose painting" or "dose sculpting" ability to further customize the delivered dose distribution. The improved capabilities of nuclear magnetic resonance imaging and spectroscopy, and of positron emission tomography, are beginning to provide physiological and functional information about the tumor and its surroundings. In addition, molecular imaging promises to reveal tumor biology at the genotype and phenotype level. These developments converge to provide significant opportunities for enhancing the success of radiotherapy. Results: The ability of IMRT to deliver nonuniform dose patterns by design brings to fore the question of how to "dose paint" and "dose sculpt", leading to the suggestion that "biological" images may be of assistance. In contrast to the conventional radiological images that primarily provide anatomical information, biological images reveal metabolic, functional, physiological, genotypic, and phenotypic data. Important for radiotherapy, the new and noninvasive imaging methods may yield three-dimensional radiobiological information. Studies are urgently needed to identify genotypes and phenotypes that affect radiosensitivity, and to devise methods to image them noninvasively. Incremental to the concept of gross, clinical, and planning target volumes (GTV, CTV, and PTV), we propose the concept of "biological target volume" (BTV) and hypothesize that BTV can be derived from biological images and that their use may incrementally improve target delineation and dose delivery. We emphasize, however, that much basic research and clinical studies are needed before this potential can be realized. Conclusions: Whereas IMRT may have initiated the beginning of the end relative to physical conformality in radiotherapy, biological imaging may launch the beginning of a new era of biological conformality. In combination, these approaches constitute MD-CRT that may further improve the efficacy of cancer radiotherapy in the new millennium. and AU: Grosu AL; Weber W; Feldmann HJ; Wuttke B; Bartenstein P; Gross MW; Lumenta C; Schwaiger M; Molls M. TI: First experience with I-123-alpha-methyl-tyrosine spect in the 3-D radiation treatment planning of brain gliomas. SO: Int J Radiat Oncol Biol Phys 2000 May 1;47(2):517-26. Abstract: PURPOSE: This study compares the results of iodine-123-alpha-methyl-tyrosine single photon computed emission tomography (IMT-SPECT) with magnetic resonance imaging (MRI) in tumor volume definition of brain gliomas. Furthermore, it evaluates the influences of the information provided from IMT-SPECT for three-dimensional (3D) conformal treatment planning. METHODS AND MATERIALS: In 30 patients with nonresected, histologically proven brain gliomas (glioblastoma-13 patients, astrocytoma Grade III-12 patients, astrocytoma Grade II-3 patients, oligodendroglioma Grade III-1 patient, oligodendroglioma Grade II-1 patient), IMT-SPECT and MRI were performed pretherapeutically in the same week. A special software system allowed the coregistration of the IMT-SPECT and MRI data. The gross tumor volume (GTV) defined on the IMT-SPECT/T2-MRI fusion images (GTV-IMT/T2) was compared with the GTV-T2, defined on the T2-MRI alone. On the IMT-SPECT/T1Gd-MRI overlays, the volume of the IMT tumor uptake (GTV-IMT) was compared with the volume of the gadolinium (Gd) enhancement (GTV-T1Gd). The initial planning target volume (PTV) and the boost volume (BV) outlined on the IMT-SPECT/T2-MRI co-images were analyzed comparatively to the PTV and BV delineated using the T2-MRI alone. RESULTS: In all 30 patients a higher IMT uptake of tumor areas, compared to the normal brain tissue was observed. Mean GTV-IMT, mean GTV-T2, and mean GTV-T1Gd were 43, 82, and 16 cm(3), respectively. IMT tumor uptake outside the contrast enhancement regions was observed in all patients. Mean relative increase of tumor volume defined on the fusion images, GTV-IMT/T1Gd versus GTV-T1Gd alone was 78%. IMT tumor uptake areas outside the GTV-T2 were registered in 7 patients (23%). In these patients, the mean increase GTV-IMT/T2 was 33% higher than GTV-T2, defined according to the T2-MRI data alone. The additional information provided by IMT-SPECT modified minimally the initial PTV (mean relative increase PTV-IMT/T2 versus PTV-T2, 5%) but significantly the BV (mean relative increase BV-IMT/T2 versus BV-T2, 37%). CONCLUSION: In a significant number of patients, the IMT-SPECT investigation improves tumor detection and delineation in the planning process. This has important consequences in the 3D conformal treatment planning, especially in the delineation of BV and in dose escalation studies. Editor's comments: Ling's article (and the accompanying editorial by Tepper) nicely summarize the crucial role biologic imaging as a complement to traditional "anatomic" imaging will occupy as our ability to conform radiation through IMRT techniques evolves. Once one can produce any dose distribution one desires through IMRT, the question of what volume to treat and to what does becomes paramount. High dose boosts (or altered fractionation schemes such as concomittant high dose per fraction boosts) to limited "biologic target volumes (BTV) may improve results. As important will be the ability to predict or track response to treatment through biologic imaging. The article by Grosu et al in last month's IJROBP is an example of the efforts to incorporate a biologic imaging modality (I-123-alpha-methyl-tyrosine spect) into the treatment planning of malignant gliomas. The clinical significance of this form of treatment planning remains to be determined however, this incorporation of biologic imaging with radiation treatment planning will continue to increase in frequency... ****************** Breast: Recht 7/00 AU: Chetty U; Jack W; Prescott RJ; Tyler C; Rodger A. TI: Management of the axilla in operable breast cancer treated by breast conservation: a randomized clinical trial. Edinburgh Breast Unit. SO: Br J Surg 2000 Feb;87(2):163-9. Abstract: BACKGROUND: In the treatment of operable breast cancer by breast conservation, the extent of axillary dissection, the need for radiotherapy to the axilla and the morbidity associated with these procedures have not been assessed adequately. METHODS: Patients with operable breast cancer were randomized to have level III axillary node clearance (232 patients) or axillary node sample (234 patients). Radiotherapy to the axilla was given selectively. Radiotherapy was not given to those who had an axillary clearance. In the early part of the study all patients who had node sample were treated by radiotherapy (54 patients); subsequently this was modified to include only those who were node positive. The morbidity to the shoulder and arm was assessed before and after operation by measuring upper limb volume and circumference, and combined glenohumeral and scapular movement and muscle power. RESULTS: Comparing the two surgical policies, no difference was found in local (axillary clearance 14 versus sample 15), axillary (eight versus seven) or distant (29 versus 29) recurrence. There was no statistically significant difference in 5-year survival rate (clearance 82.1 versus sample 88.6 per cent). Morbidity was least in those who had a node sample and no radiotherapy to the axilla. Radiotherapy to the axilla in patients who had a node sample resulted in a significant reduction in range of movement of the shoulder, e.g. mean(s.e.) 2.2(0.6) cm reduction in lateral rotation at 3 years. Surgical axillary clearance was associated with significant lymphoedema of the upper limb, e.g. 4.1(0.7) per cent increase in arm volume at 3 years. CONCLUSION: A selective policy for the management of the axilla is associated with no increase in axillary recurrence or mortality rate compared with routine axillary node clearance. Patients who are node negative after axillary sample can avoid radiotherapy or axillary clearance. Editor's comments: This very important trial conducted in Edinburgh, Scotland between 1987-95 repeated the schema of an earlier trial performed in patients undergoing mastectomy (Br J surg 1995;82:1504-8). The conclusions of the two trials were the same. That is, axillary and other failure rates were the same in patients undergoing complete axillary dissection (Levels I-III) and those undergoing axillary sampling with radiotherapy given to patients with positive nodes. The obvious implication for patients with a positive sentinal node biopsy is that they could be treated with axillary radiotherapy, rather than completion dissection (see my review in J Surg Oncol 1999:72:184-92 for further discussion). It is not clear that RT will be effective in all such patients, however (see the JCRT experience following limited axillary surgery in the Int J Radiat Oncol Biol Phys 1999;45(suppl):156-6). (Whether any additional axillary treatment - beyond that provided by breast tangential fields - is needed is controversial and is the subject of the American College of Surgeons Oncology Group Trial Z0011.) The use of this particular study to justify such an approach is also limited by two other factors. First, a substantial proportion of the population (48 patients, including 5 patients with positive nodes) did not recieve RT at all, and the use of axillary RT was somewhat consistent in both arms. Second, the morbidity of axillary RT in this trial was substantial with regards to the range of motion of the shoulder. This may have been because of the use of large fraction sizes and total doses and the technique chosen (45 Gy in 2.25-Gy fractions and the use of a posterior axillary boost). Of note, arm edema was increased substantially by complete dissection. The issue of whether axillary RT can replace completion Level I-II following a positive SNB will eventually need to be tested in randomized trials. ****************** RES: Hoppe 7/00 No Reference Selected ****************** Lung/Mediastinum: Turrisi 7/00 No Reference Selected ****************** GU: Roach 7/00 AU: Fiveash JB; Hanks G; Roach M; Wang S; Vigneault E; McLaughlin PW; Sandler HM. TI: 3D conformal radiation therapy (3DCRT) for high grade prostate cancer: a multi-institutional review. SO: Int J Radiat Oncol Biol Phys 2000 May 1;47(2):335-42. Abstract: PURPOSE: To evaluate the results of 3DCRT and the effect of higher than traditional doses in patients with high grade prostate cancer, we compiled data from three institutions and analyzed the outcome of this relatively uncommon subset of prostate cancer patients. METHODS AND MATERIALS: The 180 patients with Gleason score 8- 10 adenocarcinoma of the prostrate were treated with 3DCRT at the University of Michigan Health System, University of California-San Francisco, or Fox Chase Cancer. Eligible patients had T1-T4 NO or NX MO adenocarcinoma with a pretreatment PSA. Pretreatment characteristics included: median age 72 years, 60.6% Gleason score 8 tumors, 57.6% T1-T2, and median pretreatment PSA 17.1 ng/ml (range 0.3-257.1). The total dose received was <70 Gy in 30%, 70-75 Gy in 37%, and >75 Gy in 33%, 27% received adju vant or neoadjuvant hormonal therapy. The median follow-up was 3.0 years for all patients and 16% of patients were followed up for at least 5 years. RESULTS: The 5-year freedom from PSA failure was 62.5% for all patients and 79.3% in T1-T2 patients. Univariate analysis revealed that T-stage (T1-T2 vs. T3-T4), pretreatment PSA, and RT dose predicted for freedom from PSA failure. 5-year overall survival for all patients was 67.3%. Only RT dose was predictive of 5-year overall survival on univariate analysis. Because a significant association was seen between T-stage and RT dose, the Cox proportional hazards model was performed separately for T1-T2 and T3-T4 tumors. None of the prognostic factors reached statistical significance for overall survival or freedom from PSA failure in T3-T4 patients or for overall survival in T1-T2 patients. Lower RT dose and higher pretreatment PSA predicted for PSA failure on multivariate analysis in T1-T2 patients. CONCLUSION: This retrospective study from three institutions with experience in dose escalation suggests a dose effect for PSA control above 70 Gy in patients with T1-T2 high grade prostate cancer. These results are superior to surgery and emphasize the need for dose escalation in treating Gleason 8-10 prostate cancer. Editor's comments: The paper by Fiveash et al. raises some interesting questions about the treatment of high grade (Gleason scores 8-10) prostate cancer. This represents the largest study published to date of patients with clinically localized high grade prostate cancer. There are three areas particularly worthy of comment: (1) outcomes compared to surgery; (2) outcomes compared to brachytherapy; and (3) evidence of a dose response. Most folks don't realize that surgical series consistently report a 75% biochemical failure rate after radical prostatectomy in unselected (mostly clinical T1-2) patients [Oefelein, 1995, Ohori, 1994, Partin, 1994]. Even among patients with pathologically confined disease more than half of patients with Gleason scores of 8-10 have failed within 5 years [Lerner, 1996]. This multi-institutional study is a follow-up of an earlier but smaller study suggesting a dose response for patients with PSAs < 20 ng/ml [Roach, 1996]. In this report, these authors note a failure rate which is more favorable than any surgical or brachytherapy series. These authors noted a 5 year bNED of 89.7% for PSAs <10 ng/ml, and for patients clinically staged as T1-2 recieving 75 Gy the two year bNED was 94.1%. It is noteworthy that the trial by Pollack et al. failed to identify this group as one that benefits selectively from dose esclation. This might well be due to the fact that unlike the entire cohort in their study that appears to benefit if their PSA is > 10 ng/ml, lower PSAs may be required to benefit from higher doses in patients with Gleason scores of 8-10. Furthermore, Pollack et al. had fewer patients with Gleason scores of 8-10, and none of them received less than 70 Gy (the group where the biggest differences in outcome were seen). Further support for a dose response with a survival benefit among patients with Gleasons scores of 8-10 was reported by Valicenti during ASCO in 1999. This retrospective study of prostate cancer patients treated with radiotherapy alone on prostate cancer trials highlights just how important this apparently steep this dose response might be! Only time will tell whether these data will really hold up. It may well be that as suggested by some authors with head and neck, and bladder cancers, high grade tumors may be more responsive to radiotherapy. The addition of hormonal therapy may further support the arguement that radiotherapy may be the treatment of choice for patients with high grade prostate cancer! ****************** Radiobiology: Withers 7/00 AU: Peacock J; Ashton A; Bliss J; Bush C; Eady J; Jackson C; Owen R; Regan J; Yarnold J. TI: Cellular radiosensitivity and complication risk after curative radiotherapy. SO: Radiother Oncol 2000 May;55(2):173-8. Abstract: PURPOSE: To test for an association between in vitro fibroblast radiosensitivity and complication risk in a case-control study of breast cancer patients treated under standard conditions in a clinical trial of radiotherapy dose fractionation. PATIENTS AND METHODS: A cohort of patients participating in a randomised clinical trial of radiotherapy dose fractionation was selected on the basis of treatment-induced changes in the breast several years later. Thirty-nine cases with marked normal tissue changes were matched on several variables with 65 controls with no changes attributable to radiotherapy. Dermal fibroblast strains were established from duplicate skin biopsies, and clonogenic cell survival assays performed in triplicate after both high (approximately 1.6 Gy/min) and low ( approximately 1 cGy/min) dose-rate irradiation. Laboratory studies were blind to patient identity, treatment outcome and radiotherapy schedule. RESULTS: Analysis of 1128 clonogenic survival curves confirmed significant inter-patient variation in fibroblast radiosensitivity as measured by clonogenic survival. However, no association between fibroblast radiosensitivity and the development of late radiotherapy normal tissue effects was detected. CONCLUSIONS: Inter-individual variation in cellular radiosensitivity may not be the main determinant of complication risk in patients undergoing radiotherapy for breast cancer. Other biological and technical factors may be more important in explaining the marked inter-patient differences in normal tissue damage evident several years after curative radiotherapy. and AU: Barber JB; Burrill W; Spreadborough AR; Levine E; Warren C; Kiltie AE; Roberts SA; Scott D. TI: Relationship between in vitro chromosomal radiosensitivity of peripheral blood lymphocytes and the expression of normal tissue damage following radiotherapy for breast cancer. SO: Radiother Oncol 2000 May;55(2):179-86. Abstract: BACKGROUND AND PURPOSE: There is a need for rapid and reliable tests for the prediction of normal tissue responses to radiotherapy, as this could lead to individualization of patient radiotherapy schedules and thus improvements in the therapeutic ratio. Because the use of cultured fibroblasts is too slow to be practicable in a clinical setting, we evaluated the predictive role of assays of lymphocyte chromosomal radiosensitivity in patients having radiotherapy for breast cancer. MATERIALS AND METHODS: Radiosensitivity was assessed using a micronucleus (MN) assay at high dose rate (HDR) and low dose rate (LDR) on lymphocytes irradiated in the G(0) phase of the cell cycle (Scott D, Barber JB, Levine EL, Burril W, Roberts SA. Radiation-induced micronucleus induction in lymphocytes identifies a frequency of radiosensitive cases among breast cancer patients: a test for predispostion? Br. J. Cancer 1998;77;614-620) and an assay of G(2) phase chromatid radiosensitivity ('G(2) assay') (Scott D, Spreadborough A, Levine E, Roberts SA. Genetic predisposition in breast cancer. Lancet 1994; 344: 1444). In a study of acute reactions, blood samples were taken from breast cancer patients before the start of radiotherapy, and the skin reaction documented. 116 patients were tested with the HDR MN assay, 73 with the LDR MN assay and 123 with the G(2) assay. In a study of late reactions, samples were taken from a series of breast cancer patients 8-14 years after radiotherapy and the patients assessed for the severity of late effects according to the 'LENT SOMA' scales. 47 were tested with the HDR assay, 26 with the LDR assay and 19 with the G(2) assay. For each clinical endpoint, patients were classified as being normal reactors or 'highly radiosensitive patients' (HR patients (Burnet NG. Johansen J, Turesson I, Nyman J. Describing patients' normal tissue reactions: Concerning the possiblity of individualising radiotherapy dose presciptions based on potential predictive assays of normal tissue radiosensitivity. Int. J. Cancer 1998;79:606-613)). RESULTS: The HR patients could be identified in some of the assays. For example, for acute skin reactions, 9/123 patients were judged as HR; they had significantly higher G(2) scores than normal reactors (P=0.004). For the late reactions, the mean HDR MN scores were higher for the 4/47 patients who had severe telangiectasia (P=0.042) and the 8/47 patients had severe fibrosis (P=0.055). However, there were no trends towards increased chromosomal radiosensitivity with the micronucleus scores at HDR or LDR, or with G(2) chromosomal radiosensitivity. CONCLUSIONS: While these results support the concept of using lymphocytes to detect elevated sensitivity to radiotherapy (as an alternative to fibroblasts), these assays are unlikely to be of assistance for the prediction of normal tissue effects in the clinic in their present form. and AU: Brock WA; Tucker SL. TI: In vitro radiosensitivity and normal tissue damage [editorial]. SO: Radiother Oncol 2000 May;55(2):93-4. Editor's comments: These two papers and associated editorial express the current thinking about predictive assays for relative radiosensitivity among patients. Overall, the intensive research on predictive assays has supported the concept that there are variations (probably mostly small) in radiosensitivity from person to person but that this cannot be measured accurately enough to be practical in individualizing treatment, except perhaps in extreme cases such as ataxia telangiectasia. ****************** Health Services Research: Hayman 7/00 AU: Lee SJ; Earle CC; Weeks JC. TI: Outcomes research in oncology: history, conceptual framework, and trends in the literature. SO: J Natl Cancer Inst 2000 Feb 2;92(3):195-204. Abstract: "Outcomes research" is a commonly used term, but what does it really mean? In this review article, we 1) briefly review the historic background of outcomes research, paying particular attention to the social and political movements that helped shape the field; 2) present a conceptual framework to help classify the major areas of research and provide a working definition of outcomes research; and 3) review the oncology literature in the English language from 1966 through 1998 to examine temporal trends and characterize the body of work being presented to the practicing oncology community. We conclude that outcomes research is a broad concept, which, in its current usage, describes an array of distinct types of research. However, common themes are apparent when outcomes research is viewed in the context of its historic origins and is contrasted with other established disciplines, especially clinical trials. Our literature review shows that outcomes studies are increasing in absolute numbers, in relative proportion of the oncology literature, and in quality. We suggest that as different branches of investigation develop their own literature and methodology-in effect, outgrowing the generic label of outcomes research-they become identified by separate, more precise terms. Editor's comments: If you have every wondered what "outcomes research" actually is (and is not), you would probably find it helpful to read this article. This review article starts out by reviewing the history of outcomes research (honorable mention goes to the Patterns of Care Studies as the first large-scale attempt to measure quality of care in oncology!). Next the authors present a "conceptual framework", in an attempt to try to explain the differences between the terms "outcomes research" and "health services research" (currently, there isn't much) and to classify the different types of studies that fall under these terms (e.g., health-related quality of life, patient preferences, decision making, costs, quality of care, access, differences in practice patterns, physician-patient relationships, decision rules, appropriate use of tests, guidelines, etc.). A useful table in this section is a listing of the MeSH terms relevant to outcomes research, which you can use when searching the MEDLINE database for references related to this topic. Lastly, the authors finish with a review of the characteristics of the "outcomes" articles that have been published in several of the more prominent journals over the last 20 years. In conclusion, I think this article does a good job of providing some basic background information about the field and gives the reader a good idea of the types of studies that are currently considered to fall under the umbrella of outcomes research. ****************** Radiation Biophysics: Chen 7/00 No Reference Selected ****************** Brian J. Goldsmith, M.D. Moderator, IROJC