From owner-radoncjc@net.bio.net Tue Jan 4 13:11:16 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 8645B17A6E; Tue, 4 Jan 2000 13:11:11 +0000 (GMT) Received: from bromine.hgmp.mrc.ac.uk (bromine [193.62.192.35]) by hgmp.mrc.ac.uk (8.9.3/8.9.3) with ESMTP id NAA19689 for ; Tue, 4 Jan 2000 13:11:08 GMT Received: (from mfaller@localhost) by bromine.hgmp.mrc.ac.uk (8.9.3+Sun/8.8.8) id NAA21801 for radoncjc-list; Tue, 4 Jan 2000 13:11:08 GMT Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id 5330017AC6; Mon, 3 Jan 2000 22:47:53 +0000 (GMT) To: nobody@hgmp.mrc.ac.uk X-Really-To: radoncjc@net.bio.net Subject: January 2000 Internet Radiation Oncology Journal Club (IROJC) Reply-To: radoncjc@hgmp.mrc.ac.uk Date: Mon, 03 Jan 2000 17:12:33 -0500 From: Brian Goldsmith Message-Id: <20000103224753.5330017AC6@mercury.hgmp.mrc.ac.uk> Sender: owner-radoncjc@net.bio.net Precedence: bulk January 2000 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 56th 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 ----------------------------------------------------- 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, with the goal of stimulating a professional discussion of these references and their subjects. ------------------------------------------------------------ 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 1/00. (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 (briandeb@bellatlantic.net) private questions and comments which are not intended for IROJC posting and public reading. ****************** Peds: Donaldson 12/99 AU: Fouladi M; Gajjar A; Boyett JM; Walter AW; Thompson SJ; Merchant TE; Jenkins JJ; Langston JW; Liu A; Kun LE; Heideman RL. TI: Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor. SO: J Clin Oncol 1999 Oct;17(10):3234-7. URL: http://www.jco.org/cgi/content/full/17/10/3234 PDF: http://www.jco.org/cgi/reprint/17/10/3234 Abstract: PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Examination of CSF for malignant cells, detection of LMD on spinal magnetic resonance imaging (MRI), or both are the methods routinely used to diagnose LMD. A recent study suggested 100% correlation between CSF and MRI findings in children with medulloblastoma. To determine the validity of this hypothesis, we compared the rate of detection of LMD between concurrent lumbar CSF cytology and spinal MRI performed at diagnosis in patients with medulloblastoma or PNET. PATIENTS AND METHODS: As a part of diagnostic staging, 106 consecutive patients newly diagnosed with medulloblastoma or PNET were evaluated with concurrent lumbar CSF cytology and spinal MRI. CSF cytology was examined for the presence of malignant cells and spinal MRI was reviewed independently for the presence of LMD. RESULTS: Thirty-four patients (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. There were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bounds on the proportion of patients with LMD whose disease would have gone undetected using either CSF cytology or MRI as the only diagnostic modality were calculated at 14.4% and 17.7%, respectively. CONCLUSION: With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET. Thus, both CSF cytology and spinal MRI should routinely be used to diagnose LMD in patients with medulloblastoma or PNET. Editor's comments: It may be tempting to avoid preforming a lumbar pucture for cytologic examination of the CSF in a baby or toddler, when one has a spinal MRI for staging. Likewise, it may be tempting to avoid ordering a Gd-enhanced MRI if one already has negative CSF cytology. This article reminds us that both studies are necessary for accurate staging of children with PNET and medulloblastoma. This article is an important companion article to that by Gajjar A et al from the same institution, which appeared in the July, 1999 IJROBP Journal club, and emphasized the importance of examining the CSF from a lumbar tap over that from a shunt, in children with brain tumors. Since the presence of leptomeningeal disease alters the management and treatment course of children with brain tumors, we must continue to preform accurate staging at the time of diagnosis, and modify treatment accordingly. ****************** Head/Neck/Skin: Foote 1/00 No Reference Selected ****************** GYN: Petereit 1/00 AU: Naumann RW; Higgins RV; Hall JB. TI: The use of adjuvant radiation therapy by members of the Society of Gynecologic Oncologists. SO: Gynecol Oncol 1999 Oct;75(1):4-9. URL: http://www.idealibrary.com/links/citation/0090-8258/75/4 PDF: http://www.idealibrary.com/links/artid/gyno.1999.5548/production/pdf Abstract: OBJECTIVES: The aim of this study was to determine the attitudes of the members of the Society of Gynecologic Oncologists with respect to the use of adjuvant radiation therapy in women with endometrial cancer. METHODS: An anonymous survey concerning the use of adjuvant radiation therapy in endometrial cancer was mailed to all members of the Society of Gynecologic Oncologists listed in the 1998 directory. RESULTS: Of the 767 listed members, 325 (42%) returned completed surveys. Less than 20% of respondents recommended adjuvant radiation therapy in stage IA grade 1 or 2 and stage IB grade 1 endometrial cancer. Adjuvant radiation is recommended by 40 to 50% of respondents in women with stage IA grade 3 and IB grade 2 tumors. Most recommend adjuvant radiation for all women with >50% myometrial invasion or grade 3 tumors with any myometrial invasion. Lymph node sampling is attempted in all cases by 48% of respondents. For those familiar with Gynecologic Oncology Group (GOG) Study No. 99, 20% stated that they were more likely to recommend adjuvant radiation and 27% stated that they were less likely to recommend adjuvant radiation based on the preliminary results. Except in stage IA grade 1 tumors, the chance of recommending further therapy in women with all stages and grades was significantly less if a complete staging procedure including lymph node dissection had been performed. CONCLUSIONS: Complete staging appears to decrease the chance that postoperative therapy will be recommended. The use of adjuvant radiation therapy seem to have declined slightly as a result of GOG Study No. 99. Future studies in women with endometrial cancer that do not require lymph node sampling should evaluate the frequency of adjuvant therapy in the absence of complete staging. Copyright 1999 Academic Press. Editor's comments: The goal of the Naumann article was to examine the attitudes of gynecologic oncologists towards the use of adjuvant radiotherapy in woman with endometrial cancer. This survey of SGO (Society of Gynecologic Oncologists) members is timely since complete surgical staging (lymphadenectomies) is being increasingly performed and the results of GOG #99 were recently presented. An excellent editorial by Cardenes and Randall also appears in the same issue of Gynecologic Oncology. As backround, GOG #99 is a phase III trial which investigated the efficacy of whole pelvic radiotherapy for completely staged patients with I and occult II disease. While there was no difference in the survival rates, there was a difference in the disease-free survival at 2 years favoring pelvic radiotherapy: 94% versus 85%. The most common site of preventable failures was the vaginal cuff. The data from GOG #99 has yet to appear in manuscript format. Interestingly, over 7 papers and/or editorials have been written which refer to this study. In the January issue of Seminars of Radiation Oncology [2000], five papers quote this data. With the above preamble out of the way, the Naumann paper revealed the following attitudes from gynecologic oncologists: 1) adjuvant radiotherapy is infrequently recommended for low-risk endometrial patients - grade 1 and 2/stage IA, and grade 1/stage IB patients 2) adjuvant vaginal cuff brachytherapy is the most common form of radiotherapy recommended for intermediate risk patients: grade 2/stage IB, and grade 3/stage IA patients 3) pelvic radiotherapy is still commonly recommended for deeply invasive tumors (stage IC) or grade 3 lesions with any myometrial invasion 4) completely staged patients with negative lymph nodes are less likely to receive adjuvant radiotherapy 5) gynecologic oncologists are "apparently" less likely to recommend adjuvant radiotherapy based on the results of GOG #99: 27% vs 20% [no p value given] 6) lymphadenectomies are being more commonly pursued 7) The majority of surgeons believe that removal of the lymph nodes is therapeutic. The study reminds me of a common cliché that states: "the more things change, the more they remain the same"! I am not sure if the recommendations for adjuvant radiotherapy have really changed: observation for low-risk patients, vaginal cuff brachytherapy for intermediate-risk patients and pelvic radiotherapy for high-risk patients. What really concerns me is the suggestion that pelvic radiotherapy can possibly be omitted for high-risk endometrial patients who are completely staged based on the results of GOG #99. The majority of patients from GOG #99 were not high risk! Only 20% had grade 3 disease, and 40% had stage IC disease. We do not know if pelvic radiotherapy can be safely omitted for high risk stage I patients, or if vaginal cuff brachytherapy can be substituted for pelvic radiotherapy. I do agree with the authors' concluding statements. They suggest a randomized trial of vaginal cuff brachytherapy versus observation for intermediate-risk endometrial patients, and pelvic radiation versus vaginal cuff brachytherapy for high-risk stage I patients. Many people have submitted these protocols, including myself, to the GOG corpus committee. Unfortunately, nobody has succeeded yet in addressing these relatively simple, but profoundly important questions. My suggestion is to keep submitting these important protocols to the GOG corpus committee -- persistence may wear them down! ****************** GI / Soft Tissue Sarcoma: Tepper 1/00 AU: Merchant NB; Lewis JJ; Woodruff JM; Leung DH; Brennan MF. TI: Extremity and trunk desmoid tumors: A multifactorial analysis of outcome. SO: Cancer 1999 Nov 15;86(10):2045-52. URL: http://canceronline.wiley.com/server-java/Arknoid/cancer/0008-543X/v86n10/v86n10p2045-frameset.html Abstract: BACKGROUND: The natural history of desmoid tumors remains an enigma. Previous reports attempting to identify their biology have included recurrent and primary tumors as well as tumors from both intra- and extra-abdominal sites. The purpose of this study was to analyze patients with primary extremity and trunk desmoid tumors treated and followed at a single institution and to determine factors influencing disease free survival. METHODS: Between July 1982 and June 1997, 189 patients with extremity and superficial trunk desmoid tumors were treated and followed prospectively. Of these, 105 presented with primary disease and formed the basis of this study. RESULTS: The median follow-up for the entire group of patients was 49 months; it was 46 months for patients who did not develop a local recurrence. During this time, 24 patients (23%) had a local recurrence. No patients died of disease. The 2-year and 5-year local recurrence free survival rates were 80% and 75%, respectively. None of the prognostic factors analyzed, including age, gender, depth of tumor, size of tumor, or tumor site, were significant for predicting local recurrence. Moreover, positive resection margins were not predictive of recurrence. The selective use of adjuvant radiation therapy did not influence the rate of local recurrence regardless of the margin status. CONCLUSIONS. Attempts to achieve negative resection margins may result in unnecessary morbidity and may not prevent local recurrence. Operations that preserve function and structure should be the primary goal, because the presence of residual disease cannot be clearly shown to impact adversely on 5-year disease free or overall survival. Editor's comments: This article continues a long trend of provocative articles from the surgical group at Memorial Sloan-Kettering. The present article deals with the treatment of desmoids of the trunk and extremities. This is a disease that is well known to act differently from the cancers that we usually treat, but it clearly can be an aggressive tumor that causes substantial morbidity if not treated properly. It is well known that desmoids will sometimes recur after surgery even when wide margins are obtained, and that they will at times not recur even when margins are positive. However, the approach that I have taken (and has been taken by many others in the rad onc community), is to irradiate postoperatively if 1) the tumor has already recurred once, 2) the treatment of a recurrence with surgery would entail substantial morbidity or 3) to use primary radiation therapy for unresectable disease. This article questions the use of any radiation therapy in the postoperative setting (although it says nothing about the use of primary radiation therapy). Basically, no factors could be found which predicted for recurrence including positive resection margins. Even in patients with positive margins the use of radiation therapy did not appear to effect the incidence of local failure. Unfortunately, the number of patients treated with radiation therapy was fairly small (31) and 40% received brachytherapy for at least part of their treatment (which extrapolating from other data might not be effective for low grade lesions such as desmoids). Also, since this study was clearly not randomized, there were probably other factors which influenced the decision to use or not to use RT. Nonetheless, this article suggests that we know even less about the biology and natural history of desmoids than we thought (and I at least didn't think we knew very much). There is no question that RT can influence the natural history of desmoids as is demonstrated by the studies that have shown good control with RT alone. The fact that often patients with macroscopic residual have no disease progression, and that treatment of recurrences don't seem to do any worse than treatment of the primary suggests that we should be considering a conservative approach to treatment. Surgery which destroys function should be used very sparingly if at all. Adjuvant radiation therapy (even for positive margins) should be used only when treatment of a recurrence would cause substantial problems. Meanwhile, we need to try to learn more about the biology of this disease which might help us develop a more rational guide to therapy. ****************** CNS: Bauman 1/00 AU: Kreth FW; Berlis A; Spiropoulou V; Faist M; Scheremet R; Rossner R; Volk B; Ostertag CB. TI: The role of tumor resection in the treatment of glioblastoma multiforme in adults. SO: Cancer 1999 Nov 15;86(10):2117-23. URL: http://canceronline.wiley.com/server-java/Arknoid/cancer/0008-543X/v86n10/v86n10p2117-frameset.html Abstract: BACKGROUND. The therapeutic impact of tumor resection is poorly defined. Therefore the current study was conducted. METHODS. A retrospective, 2-institutional study was conducted (1991-1994) to compare the treatment results of stereotactic biopsy plus radiation therapy (99 patients; tumor dose: 60 gray [Gy]) with those of surgical resection plus radiation therapy (126 patients; tumor dose: 60 Gy). Only adult patients with supratentorial, lobar located, de novo glioblastoma were included. Survival time was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from the multivariate Cox proportional hazards model. RESULTS. Patients were categorized in the Radiation Therapy Oncology Group (RTOG) Classes IV (46 patients), V (157 patients), and VI (22 patients). The resection group and the biopsy group did not differ in terms of age, pretreatment Karnofsky performance status (KPS), gender, duration of symptoms, presenting symptoms, tumor location, tumor size, and the frequency of midline shift. Patients in the biopsy group more often were found to have left-sided tumors (P less than 0.001). Transient perioperative morbidity and mortality rates were 1% and 1%, respectively, in the biopsy group and 5% and 1.6%, respectively, in the resection group (P greater than 0.05). The median survival time was 37 weeks for the resection group and 33 weeks for the biopsy group. The difference was not statistically significant (P equals 0.09). The most favorable pretreatment prognostic factor was patient age less than 60 years (P less than 0.01). Tumor resection was highly effective in patients with midline shift (P less than 0.01). In patients without midline shift radiation therapy alone was found to be as effective as tumor resection plus radiation therapy (P equals 0.5). Patients with midline shift were more likely to have a worse KPS during the course of primary radiation therapy (P less than 0.05). CONCLUSIONS. For RTOG Classes IV-VI patients with moderate mass effect of the tumor, radiation therapy alone is a rational treatment strategy. Tumor resection should be performed in patients with pretreatment midline shift whenever possible. Editor's comments: This study attempts to identify the benefit of surgical resection versus biopsy among patients with glioblastoma. While they did not specifically exclude younger patients, the patient population was made up of RTOG RPA groups IV-VI, that is patients age less than 50 with a KPS less than 90 (gp IV) and patients age greater than 50 (gps IV-VI). Thus any conclusions drawn from the paper may not be applicable to younger patients with good KPS. They found that the benefit of a decompressive/cytoreductive surgical resection + radiation vs. stereotactic biopsy + radiation was most pronounced among those patients presenting with symptoms of mass effect at diagnosis as evidenced by a midline shift greater than 5mm on CT or MRI pre-treatment. They also noted an early improvement/stabilization in KPS with decompressive surgery but by the end of radiotherapy, KPS stabilization/improvement was equivalent between the resection versus biopsy groups. This paper suggests that a conservative approach to older/poor prognostic patients with GBM by stereotactic biopsy and radiation may be feasible and as effective as surgical resection (with its potential morbidities) as long as mass effect from the tumor is not too severe (no midline shift). Given that many of these people might be better treated with shorter courses of palliative radiotherapy, a more conservative approach to the diagnosis might be more appropriate. This study does not answer the question about what is best for the younger patient with a GBM. Our approach is to recommend a surgical decompression/resection whenever this can be done without excessive anticipated morbidity for younger patients. It is interesting to note the absence of RTOG Grp III patients in this report. One wonders if some of the Grp IV patients (age less than 50, KPS less than 90) in the biopsy only group might have been Grp III pre-radiation if a resection had been performed, given the early KPS improvement in the resected patients. An imbalance in the numbers of younger patients may have biased the results among the biopsy only group. That being said, the median age between the two groups (resection versus biopsy) was the same, so it is difficult to know the answer. They did find that, in a multivariate model, age and surgery vs. biopsy among patients with midline shift were independant predictors of outcome. Would it be possible to do a randomized study of resection vs. biopsy in patients with suspected GBM and minimal mass effect? Probably not. This study, although not randomized, does give some reassurance that biopsy plus radiation may be a safe, conservative, minimal morbidity option for the older patient with a malignant glioma. ****************** Breast: Recht 1/00 AU: Tan JE; Orel SG; Schnall MD; Schultz DJ; Solin LJ. TI: Role of magnetic resonance imaging and magnetic resonance imaging-- guided surgery in the evaluation of patients with early-stage breast cancer for breast conservation treatment. SO: Am J Clin Oncol 1999 Aug;22(4):414-8. Abstract: Magnetic resonance imaging (MRI) may be more sensitive than mammography for detecting breast cancer and may have an adjunctive role in assessing patients with early-stage disease for breast conservation treatment. This study was performed to analyze the impact of breast MRI on the clinical management of 83 patients being considered for breast conservation treatment. Eighty-three consecutive cases of patients undergoing breast MRI during standard workup and evaluation for breast conservation treatment from 1993 to 1996 were retrospectively reviewed. Records were reviewed for patient and tumor characteristics, mammographic findings, MRI findings, timing of MRI study, findings from MRI-guided surgery (when done), and whether the patient underwent breast conservation treatment. MRI definitely altered management in 15 patients (18%), may have affected management in 4 patients (5%), and did not change management in 64 patients (77%). Thirteen patients underwent additional surgery because of MRI findings; the positive predictive value for MRI-guided surgery was 38% (5 of 13). Ultimately, 82% of the patients received breast conservation treatment. No predictive factor was identified to characterize the patients most likely to have management affected by MRI findings. These findings suggest that breast MRI may be useful in the evaluation of patients with early-stage breast cancer for breast conservation treatment. A larger study population and outcome data will be required to confirm these findings and to define those patients most likely to benefit from breast MRI. Editor's comments: Much of the most important work on the use of MRI in breast imaging has been performed at the University of Pennsylvania. This paper analyzes how MRI fits into the management of patients being considered for breast-conserving therapy. It is one of the largest a number of works in this area (e.g. an earlier paper form the Penn group, Radiology 1995;196:115-122; and a nice study of its use in patients with lobular histology from the University of Arkansas group, AJR 1996;1415-19). The analysis is very well performed. Of note, only 3 of 83 patients included in this series were converted to a mastectomy as a result of the MRI findings (a lower incidence than in some other studies). However, one of these was a patient with a false-positive MRI finding; as in other series, MRI findings are not always reliable therefore. Although this is an important study, there are limitations to it that need to be kept in mind. First, the population was quite heterogeneous. Second, although they rightly include all consecutive patients who underwent MRI from 1993-96, certainly there were far more patients evaluated at Penn for BCT during that period who did not undergo MRI. It is not clear what selection factors were at work. Hence, the study population may have differed substantially from the rest of the patient pool, and thus the generalizability of these findings (like those of all other studies of this tool) are suspect. Until the very expensive, labor-intensive study of a very large truly consecutive series of patients who are candidates for BCT is done, there will remain considerable uncertainty as to the true role of MRI in this context. ****************** RES: Hoppe 1/00 AU: Harris NL; Jaffe ES; Diebold J; Flandrin G; Muller-Hermelink HK; Vardiman J; Lister TA; Bloomfield CD. TI: World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues: Report of the Clinical Advisory Committee Meeting-Airlie House, Virginia, November 1997. SO: J Clin Oncol 1999 Dec;17(12):3835-3849. URL: http://www.jco.org/cgi/content/full/17/12/3835 PDF: http://www.jco.org/cgi/reprint/17/12/3835 Abstract: PURPOSE: The European Association of Hematopathologists and the Society for Hematopathology have developed a new World Health Organization (WHO) classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell neoplasms. DESIGN: Ten committees of pathologists developed lists and definitions of disease entities. A clinical advisory committee (CAC) of international hematologists and oncologists was formed to ensure that the classification would be useful to clinicians. The CAC met in November 1997 to discuss clinical issues related to the classification. RESULTS: The WHO uses the Revised European-American Lymphoma (REAL) classification, published in 1994 by the International Lymphoma Study Group, to categorize lymphoid neoplasms. The REAL classification is based on the principle that a classification is a list of "real" disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one gold standard. The WHO classification applies the principles of the REAL classification to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. At the CAC meeting, which was organized around a series of clinical questions, participants reached a consensus on most of the questions posed. They concluded that clinical groupings of lymphoid neoplasms were neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors, such as the International Prognostic Index. CONCLUSION: The WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies. Editor's comments: Here, finally, is a summary presentation of the newest (WHO) Classification of "Neoplastic diseases of the Hematopoietic and Lymphoid Tissues". Note some key conceptual changes compared to previous classification systems used widely in the US. It includes not only the non-Hodgkin's lymphomas, but also multiple myeloma, the leukemias and Hodgkin's Disease (Hodgkin's lymphoma, for those not bound to the historical significance of HD). This makes for a relatively lengthy list of diseases, impossible for the novice (or even the expert) to commit to memory. But, the more common of the lymphoid neoplasms (in bold-face type in Table 2) are only 15 in number, and 4 of these (multiple myeloma,B-ALL, NSHD and MCHD) we wouldn't ordinarily include as non-Hodgkin's lymphomas. The eleven remaining diseases are important entities biologically and clinically. They are classified as B cell or T cell. B cell entities include small lymphocytic lymphoma, MALT, follicular lymphoma, mantle-cell, diffuse large B-cell, and Burkitt's. The T-cell diseases include T-lymphoblastic, MF, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma. The text provides an excellent summary of key issues that were discussed at the meeting at Airlie House, Virginia, two years ago. This paper is recommended as essential reading for any radiation oncologist involved in the management of patients with lymphoma. ****************** Lung/Mediastinum: Turrisi 1/00 AU: Sawyer TE; Bonner JA; Gould PM; Deschamps C; Lange CM; Li H. TI: Patients with stage I non-small cell lung carcinoma at postoperative risk for local recurrence, distant metastasis, and death: implications related to the design of clinical trials. SO: Int J Radiat Oncol Biol Phys 1999 Sep 1;45(2):315-21. Abstract: PURPOSE: Patients with pathologically staged American Joint Committee on Cancer stage I (T1 N0 or T2 N0) non-small cell lung cancer have a favorable prognosis after complete surgical resection compared with patients with more advanced stages. Benefits of adjuvant therapy in this setting are unproved. However, there may be subgroups of patients with stage I disease at high enough risk for local recurrence to prompt consideration of adjuvant or neoadjuvant radiation therapy. Likewise, there may be subgroups of patients at high enough risk for distant metastasis to justify the evaluation of chemotherapy. METHODS AND MATERIALS: From 1987 through 1990, 370 patients undergoing gross total resection of non-small cell lung cancer had stage I disease and received no chemotherapy or radiation therapy as part of their primary treatment. These patients were the subject of a retrospective review to separate patients into high-, intermediate-, and low-risk groups with respect to freedom from local recurrence (FFLR), freedom from distant metastasis (FFDM), and overall survival by using a regression tree analysis. RESULTS: The 5-year rates of FFLR, FFDM, and survival were 85%, 83%, and 66%, respectively. Regression analyses revealed that the factors independently predicting for a poorer FFLR rate included fewer than 15 lymph nodes dissected and pathologically evaluated (p equals 0.002) and the presence of a T2 tumor (p equals 0.04). Factors independently predicting for a poorer FFDM rate included a maximal dimension greater than 5 cm (p equals 0.02) and nonsquamous histology (p equals 0.03). Factors independently predicting for a poorer survival rate included fewer than 15 lymph nodes dissected and pathologically evaluated p equals 0.001) and a maximal dimension greater than 3 cm (p equals 0.003). Regression tree analyses were used to separate patients into risk groups. CONCLUSION: Incorporating the aforementioned factors into regression tree analyses, three risk groups were identified with respect to FFLR. Two each were identified for FFDM and for survival. For each of these three end- points, the differences in outcomes for each risk group were found to be both statistically and clinically significant. These risk groups may be useful in the future design of phase III trials evaluating the use of adjuvant chemotherapy and radiation therapy in the stage I setting. Editor's comments: This reports an analysis from the Mayo Clinic's resected patients with "complete dissections" found to be N-0. The patterns of failure are analyzed and factors related to local failure, distant failure, and survival. Factors of import identified from this study are tumor size and number of nodes dissected, from which the authors suggest that "extent" of dissection and its "completeness" may add to therapeutic benefit. Also of interest is what was not important: grade of tumor, and curiously non-squamous histology tended to fare better. As I cut my teeth on lung cancer over 20 years ago, I vividly remember advocating for more than palpation to be the standard procedure at time of resection for lung cancer. As the new kid on the block at a prestigious eastern ivy league center, the suggestion was dismissed and the idea that an upstart might be on to something was barely considered. Now we have some evidence that not only nodal sampling, but at least a reasonably large sample may be important in disease management. Some suggest that the dissection provides a "necessary therapy", others that the larger sampling may better categorize patients. Regardless, palpation is out and sampling seems to be standard. The article addresses a pet peeve of mine -- tumor size IS important. Since it is important, why is not part of the staging system? The recent revision of the International System is again based on a retrospective analysis of surgical patients. The subtle changes are meant for the surgeon. The attempts to use this staging system in a prospective way leads to fractious tumor board discussions as we all contort in many uncomfortable positions in attempt to apply this system prospectively for pre-treated cases. Maybe we can get a more reasonable system to use prospectively that includes size. The holy grail of translational research will be application of molecular features to aid in identifying adjuvant therapy candidates. As this article points out, even at a large referral center where the patients pay their way to get therapy from the best and the brightest, only 60 - 70 % are cured long term. Some of these patients fail in nodes alone or at the bronchial stump (the article could have been clearer about competing risks and whether these patients ultimately had local disease alone or later distant failure). Many fail distantly. But some do fine with the local therapy alone. It would be a great aid to know which subgroup requires more intense therapy, and whether more intense therapy makes a difference. Happy New Millennium to you all a year early! ****************** GU: Roach 1/00 No Reference Selected ****************** Radiobiology: Withers 1/00 AU: Terahara A; Niemierko A; Goitein M; Finkelstein D; Hug E; Liebsch N; O'Farrell D; Lyons S; Munzenrider J. TI: Analysis of the relationship between tumor dose inhomogeneity and local control in patients with skull base chordoma. SO: Int J Radiat Oncol Biol Phys 1999 Sep 1;45(2):351-8. Abstract: PURPOSE: When irradiating a tumor that abuts or displaces any normal structures, the dose constraints to those structures (if lower than the prescribed dose) may cause dose inhomogeneity in the tumor volume at the tumor-critical structure interface. The low-dose region in the tumor volume may be one of the reasons for local failure. The aim of this study is to quantitate the effect of tumor dose inhomogeneity on local control and recurrence-free survival in patients with skull base chordoma. METHODS AND MATERIALS: 132 patients with skull base chordoma were treated with combined photon and proton irradiation between 1978 and 1993. This study reviews 115 patients whose dose-volume data and follow-up data are available. The prescribed doses ranged from 66.6 Cobalt-Gray-Equivalent (CGE) to 79.2 CGE (median of 68.9 CGE). The dose to the optic structures (optic nerves and chiasm), the brain stem surface, and the brain stem center was limited to 60, 64, and 53 CGE, respectively. We used the dose-volume histogram data derived with the three-dimensional treatment planning system to evaluate several dose-volume parameters including the Equivalent Uniform Dose (EUD). We also analyzed several other patient and treatment factors in relation to local control and recurrence-free survival. RESULTS: Local failure developed in 42 of 115 patients, with the actuarial local control rates at 5 and 10 years being 59% and 44%. Gender was a significant predictor for local control with the prognosis in males being significantly better than that in females (P equals 0.004, hazard ratio equals 2.3). In a Cox univariate analysis, with stratification by gender, the significant predictors for local control (at the probability level of 0.05) were EUD, the target volume, the minimum dose, and the D5cc dose. The prescribed dose, histology, age, the maximum dose, the mean dose, the median dose, the D90% dose, and the overall treatment time were not significant factors. In a Cox multivariate analysis, the models including gender and EUD, or gender and the target volume, or gender and the minimum target dose were significant. The more biologically meaningful of these models is that of gender and EUD. CONCLUSION: This study suggests that the probability of recurrence of skull base chordomas depends on gender, target volume, and the level of target dose inhomogeneity. EUD was shown to be a useful parameter to evaluate dose distribution for the target volume. Editor's comments: Treating chordomas at the base of the skull demands some heterogeneity in dose distribution if the intent is to maximize tumor dose and minimize the dose to structures at the base of the brain. The authors point out that, even with standard "homogeneous"-dose treatment plans, the variation in dose in the tumor volume is a cause for some of the flatness of dose response (TCP) curves. Besides reporting the control rates, and that women did not respond as well as men, the authors analyzed the responses in terms of "effective uniform dose," which is the dose, which if given uniformly to the tumor would produce the same control rate as obtained with the inhomogeneous dose used. The EUD incorporates radiobiological concepts and is a good attempt at refining the dose actually "perceived by" the tumor (or normal tissue). Besides the range of physical doses distributed throughout the volume of interest, the EUD can allow for changes in fraction size, clonogen number and density, tumor growth, variation in radiosensitivity and, most importantly, the volume of tumor under or over-dosed, and the extent of the under- or over-dosage. This, and the referenced papers describing the development of the concept of EUD, are obviously important for any radiation oncologist dealing with conformal therapy and/or IMRT. It will become part of everyday practice as we think more in terms of dose volume histograms rather than such things as minimum tumor dose. ****************** Health Services Research: Hayman 1/00 AU: Gralla RJ; Osoba D; Kris MG; Kirkbride P; Hesketh PJ; Chinnery LW; Clark-Snow R; Gill DP; Groshen S; Grunberg S; Koeller JM; Morrow GR; Perez EA; Silber JH; Pfister DG. TI: Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. SO: J Clin Oncol 1999 Sep;17(9):2971 URL: http://www.jco.org/cgi/content/full/17/9/2971 PDF: http://www.jco.org/cgi/reprint/17/9/2971 and AU: Hensley ML; Schuchter LM; Lindley C; Meropol NJ; Cohen GI; Broder G; Gradishar WJ; Green DM; LangdonRJ Jr; Mitchell RB; Negrin R; Szatrowski TP; Thigpen JT; Von Hoff D; Wasserman TH; Winer EP; Pfister DG. TI: American society of clinical oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. SO: J Clin Oncol 1999 Oct;17(10):3333-55 URL: http://www.jco.org/cgi/content/abstract/17/10/3333 PDF: http://www.jco.org/cgi/reprint/17/10/3333 Abstract: PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration–approved agents that have potential chemotherapy- and radiotherapy-protectant activity—dexrazoxane, mesna, and amifostine—and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m2/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplanta-tion setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m2 or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m2 of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemotherapy. (2) Although amifostine may be considered for the reduction of neutropenia in patients receiving alkylating agents, chemotherapy dose reduction or growth factor use should be considered as an alternative to the use of amifostine. (3) Present data are insufficient to recommend the use of amifostine for protection against thrombocytopenia or the routine use of amifostine to prevent cisplatin-associated neurotoxicity or ototoxicity. Similarly, present data are insufficient to support the use of amifostine for the prevention of paclitaxel-associated neurotoxicity. (4) Use of amifostine may be considered to decrease the incidence of acute and late xerostomia in certain patients undergoing fractionated radiation therapy in the head and neck region, although present data are insufficient to recommend the use of amifostine to prevent radiation therapy–associated mucositis. Details regarding dose and management of amifostine side effects, including hypotension, are included in the guidelines. Further research is warranted to further define the role of these chemotherapy- and radiotherapy-protectant agents in the care of cancer patients. Editor's comments: This month I have selected two articles that describe the process and evidence used by two panels sponsored by ASCO to develop guidelines for the use of antiemetics and protective agents (i.e., Mesna, Dexrazoxane and Amifostine) during treatment with chemotherapy and radiation therapy. Given the source of the guidelines and the composition of the panels, it should come as no surprise that they primarily deal with issues related to medical oncology. However, both papers do describe the process used by ASCO in developing these guidelines, including how the panels were formed, the strategies used to search the literature for pertinent articles, the "levels" of evidence used to evaluate the types of studies published (e.g., meta-analysis, randomized trials, cohort studies, case reports, etc.), the "grades" or strengths of the recommendations issued and the process used in peer-reviewing the guidelines. It should be noted that although a framework exists for searching and evaluating the literature, both sets of guidelines were ultimately based on the consensus of a group of experts. It is also important to point out that the guidelines go to great lengths to emphasize that their use is voluntary, that the ultimate decision regarding their use should be made by a physician in light of each individual patient's circumstances and that guidelines, through their review and synthesis of the latest literature, should also serve to identify important questions for further research. In addition to describing the methods used to create their guidelines, it is this last point, I believe, that make these articles useful. In reviewing the relevant literature, it quickly becomes apparent that few large randomized studies have been published that help us to define the proper use of these supportive agents in radiation oncology. Hopefully these guidelines will help to stimulate trials intended to address this important issue. ****************** Happy New Year! Brian J. Goldsmith, M.D. Moderator, IROJC