From daemon Wed Jul 7 09:04:16 1999 Received: (from daemon@localhost) by net.bio.net (8.9.1a/8.9.1) id JAA03409; Wed, 7 Jul 1999 09:04:16 -0700 (PDT) Message-Id: <199907071604.JAA03409@net.bio.net> To: radoncjc@net.bio.net Date: Wed, 7 Jul 1999 05:35:24 -1000 Reply-To: radoncjc@net.bio.net From: Brian J Goldsmith Subject: July 1999 Internet Radiation Oncology Journal Club (IROJC) July 1999 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 50th 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 Jim Purdy, Ph.D. Editor, Radiation Oncology Physics and Dosimetry ----------------------------------------------------- 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 POSTINGS and commentary are available on the World Wide Web! Look for them on http://www.bio.net/ Click on the "Access the BIOSCI/bionet Newsgroups" hyperlink, and then go to "RADIATION-ONCOLOGY/Prototype". Or directly access the RADIATION-ONCOLOGY folder at http://www.bio.net/hypermail/RADIATION-ONCOLOGY/ There's also a freeWAIS search tool at the website, for searching archived postings for keywords or phrases! ------------------------------------------------------------ Commentary Rules: (1) Please cite the subject category in the header of your e-mail message, e.g., Subject: CNS 7/99. (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 7/99 AU: Gajjar A, Fouladi M, Walter AW, Thompson SJ, Reardon DA, Merchant TE, Jenkins JJ, Liu A, Boyett JM, Kun LE, Heideman RL. TI: Comparison of lumbar and shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with brain tumors. SO: J Clin Oncol 1999 17(6):1825. URL: http://www.jco.org/cgi/content/abstract/17/6/1825 Abstract: PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary CNS tumors. Cytologic examination of lumbar CSF is routinely used to detect LMD. To determine whether examination of CSF obtained from ventricular shunt taps is a more sensitive method of detecting LMD in these patients, we designed a prospective study to compare the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal (VP) shunt taps. PATIENTS AND METHODS: As a part of diagnostic staging, follow-up testing, or both, 52 consecutive patients underwent concurrent lumbar and shunt taps on 90 separate occasions, ranging from the time of diagnosis to treatment follow-up. CSF from both sites was examined cytologically for malignant cells. RESULTS: The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n equals 29), astrocytoma (n equals 10), ependymoma (n equals 5), germinoma (n equals 3), atypical teratoid rhabdoid tumor (n equals 2), choroid plexus carcinoma (n equals 2), and pineoblastoma (n equals 1). Each site yielded a median CSF volume of 1.0 mL. Fourteen of 90 paired CSF test results were discordant: in 12, the cytologic findings from shunt CSF were negative for malignant cells, but those from lumbar CSF were positive; in two, the reverse was true. Malignant cells were detected at a higher rate in lumbar CSF than in shunt CSF (P equals .0018). When repeat analyses were excluded, examination of lumbar CSF remained significantly more sensitive in detecting malignant cells (P equals .011). Analysis of the subset of patients with embryonal tumors showed similar results (P equals .0008). CONCLUSION: Cytologic examination of lumbar CSF is clearly superior to cytologic examination of VP shunt CSF for detecting leptomeningeal metastases in pediatric patients with primary CNS tumors. Editor's comments: As many of the CNS tumors affecting children have the potential to spread via the neuraxis, this paper delivers an important message of reminding all physicians who prescribe radiotherapy to children of the importance to obtain a diagnostic CSF sample from a lumbar tap, and not to reply on a CSF sample obtained solely from a ventricular shunt. To do so runs a significant risk of inadequate staging, and ultimately inadequate treatment. ****************** Head/Neck/Skin: Foote 7/99 No Reference Selected ****************** GYN: Petereit 7/99 No Reference Selected ****************** GI / Soft Tissue Sarcoma: Tepper 7/99 AU: Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ. TI: Extended lymph-node dissection for gastric cancer. Dutch Gastric Cancer Group. SO: N Engl J Med 1999 Mar 25;340(12):908-14. URL: http://www.nejm.org/content/1999/0340/0012/0908.asp Abstract: BACKGROUND: Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery. METHODS: Between August 1989 and July 1993, a total of 996 patients entered the study. Of these patients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatment with curative intent, and 285 received palliative treatment. The procedures for quality control included instruction and supervision in the operating room and monitoring of the pathological results. RESULTS: Patients in the D2 group had a significantly higher rate of complications than did those in the D1 group (43 percent vs. 25 percent, P<0.001), more postoperative deaths (10 percent vs. 4 percent, P equals 0.004), and longer hospital stays (median, 16 vs. 14 days; P<0.001). Five-year survival rates were similar in the two groups: 45 percent for the D1 group and 47 percent for the D2 group (95 percent confidence interval for the difference, -9.6 percent to +5.6 percent). The patients who had R0 resections (i.e., who had no microscopical evidence of remaining disease), excluding those who died postoperatively, had cumulative risks of relapse at five years of 43 percent with D1 dissection and 37 percent with D2 dissection (95 percent confidence interval for the difference, -2.4 percent to +14.4 percent). CONCLUSIONS: Our results in Dutch patients do not support the routine use of D2 lymph-node dissection in patients with gastric cancer. Editor's comments: This article is unusual in that the investigators performed a prospective randomized trial of two surgical techniques with what appears to be good quality control. To actually perform a trial of this sort is unusual and the authors deserve a lot of credit. What is interesting from the radiation oncologists' viewpoint is the information it gives on the possible impact of local control on improving survival in this disease. Clearly, with the overall results being negative, it does not raise too much optimism that increasing local aggressiveness will improve the end results. However, it is possible that the results were substantially skewed by the high operative mortality of 10% with the D2 dissection (compared to 4% in the control arm). Interestingly, if one looks at the risk of relapse, after 2 years the curves appear to diverge and the long term tumor control results favors the more aggressive surgical therapy. So, perhaps increasing local aggressiveness of therapy will improve survival. The radiation therapy question may be answered by the Intergroup trial that tested standard surgery +/- RT + chemo. The preliminary results of this study should be available before too long. ****************** CNS: Bauman 7/99 AU: Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ. TI: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. SO: J Clin Oncol 1999 Mar;17(3):832-45. URL: http://www.jco.org/cgi/content/abstract/17/3/832 Abstract: PURPOSE: From 1986 to 1992, "eight-drugs-in-one-day" (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB). PATIENTS AND METHODS: Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years. RESULTS: Survival and progression-free survival (PFS) +/- SE at 7 years were 55%+/-5% and 54%+/-5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63%+/-5% versus 45%+/-5%, respectively (P equals .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of PFS, compared with children 3 years old or older (P equals .0014; 32%+/-10% v 58%+/-4%, respectively). For MB patients 3 years of age or older, the prognostic effect of tumor spread (MO v M1 v M2+) on PFS was powerful (P equals.0006); 5-year PFS rates were 70%+/-5%, 57%+/-10%, and 40%+/-8%, respectively. PFS distributions at 5 years for patients with M0 tumors with less than 1.5 cm2 of residual tumor, versus greater than or equal to 1.5 cm2 of residual tumor by scan, were significantly different (P equals .023; 78%+/-6% v 54%+/-11%, respectively). CONCLUSION: VCP plus XRT is a superior adjuvant combination compared with 8-in-1 chemotherapy plus XRT. For patients with M0 tumors, residual tumor bulk (not extent of resection) is a predictor for PFS. Patients with M0 tumors, greater than or equal to 3 years with less than or equal to 1.5 cm2 residual tumor, had a 78%+/-6% 5-year PFS rate. Children younger than 3 years old who received a reduced XRT dosage had the lowest survival rate. Editor's comments: This paper deserves a careful read as it summarizes a number of important issues in the treatment of so called 'high risk' medulloblastoma treated with the benefit of contemporary (late 80's early 90's) neuro-imaging and surgical techniques. Eligibility criteria for the trial were children ages 1.5-21 years with subtotally resected (>1.5cm2 residual tumor) or locally advanced (Chang stage T3a,b/T4) or disseminated (M+) medulloblastoma. All patients were staged with early (<6 days postop) postoperative CT or MRI to measure residual disease and had spinal axis staging with CSF cytology and imaging (myelography or spinal CT/MRI). The main finding of the study was inferior progression free survival for the 8-in-1 day chemotherapy regimen compared to the 'standard' vincristine, CCNU prednisone combination. In addition, the 8-in-1 combo was associated with more toxicity. While it is not clear exactly why the 8-in-1 combination produced inferior results the authors hypothesize that a reduction in the dose intensity of vincristine, a delay in the start of radiotherapy (on average 32 days) or an 'effect of timing' (presumably inducing accelerated repopulation) may have all contributed. These results echo other chemotherapy trials were the potential benefits of complex multidrug 'non-cross resistant' regimens may be offset by a decrease in dose intensity of individual active agents and neoadjuvant therapy offset by accelerated repopulation (and/or a delay in the delivery of the more effective of two adjuvant therapies). The importance of extent of residual tumor (among the M0 but not M+ population); M stage and age (but not T stage) in predicting PFS survival following radiation and chemotherapy are also summarized in the study. A multivariate analysis of these factors would help to sort out the relative importance of these factors (particularly for the T-stage), presumably this will be the topic of another paper. The discussion elaborates on the importance of these prognostic factors and emphasizes the importance of thorough neuro-axis staging, maximal tumor resection and adequate XRT dose in the treatment of these patients. ****************** Physics/Dosimetry: Purdy 7/99 No Reference Selected ****************** Breast: Recht 7/99 AU: Esserman L, Hylton N, Yassa L, Barclay J, Frankel S, Sickles E. TI: Utility of magnetic resonance imaging in the management of breast cancer: evidence for improved preoperative staging. SO: J Clin Oncol 1999 17(1): 110 URL: http://www.jco.org/cgi/content/abstract/17/1/110 Abstract: PURPOSE: The staging and treatment for breast cancer are changing; there is an increase in the incidence of ductal carcinoma-in-situ, the use of fine-needle aspiration and stereotactic biopsy for diagnosis, and the use of neoadjuvant chemotherapy. Thus, there is a need for a tool to assess more precisely the extent of cancer in the breast before surgery. To better plan surgical and chemotherapeutic interventions, we evaluated high-resolution magnetic resonance imaging (MRI) as such a tool. PATIENTS AND METHODS: Fifty-seven patients with 58 cases of breast cancer were evaluated preoperatively with MRI using a technique called the triple-acquisition rapid gradient echo technique to maximize anatomic detail. Imaging results were compared with mammography and subsequent pathology results. RESULTS: Magnetic resonance imaging correctly identified residual or primary cancer in 55 of 58 cases and accurately predicted the extent of the cancer in 54 of 58 cases. The anatomic extent was more accurately defined with MRI compared with mammography (98% v 55%). Magnetic resonance imaging added the greatest value in cases of multifocal disease. CONCLUSION: By applying MRI selectively to patients with a known diagnosis of cancer and focusing on defining the extent of malignant lesions, we were able to obtain clear and accurate anatomic information. Our results suggest that MRI could provide very valuable information for preoperative planning and single-stage resection in breast cancer. Based on preliminary data from our series, MRI would be valuable as a staging tool in the preoperative setting even if the cost is in the range of $1,300 to $2,000. It is already significantly less than the target cost, so it is reasonable to refine this technique for clinical use to help plan the most appropriate surgical intervention and possibly reduce costs as well. A careful prospective study is warranted to validate our findings. Editor's comments: This excellent study is an important contribtion to the growing literature on the use of MRI in assessing patients with breast cancer preoperatively. The reader should also look at their related article on the relationship of MRI findings with histology and angiogenesis in The Breast Journal 1999;5:13-21.) However, the practical implications of these studies (including the present one) are not yet entirely clear to me. One important potential role of MRI (which might justify its substantial current cost) is in accurately delineating the extent of the tumor, so as to either avoid the need for reexcision by allowing the surgeon to achieve adequate margins on the first excision, or to show that the tumor is so extensive that a mastectomy should be performed, rather than breast-conserving surgery. However, it is not clear how effective MRI is in this role. First, most series find a 10-20% incidence of areas of false-positive enhancement on MRI (when compared to the ultimate patholgic findings). Second, there are few data yet as to how closely the boundaries of the lesion on MRI correspond to the microscopic pathologic findings, particularly for patients who have DCIS or an invasive ductal carcinoma with an extensive intraductal component. these latter patients are the ones in whom MRI might make the greatest difference, but they are also the ones in whom MRI might have the greatest difficulty in accurately assessing tumor spread. Until further studies particularly directed at these lesions are performed (and ultimately a randomized trial of the use of MRI in this setting), I believe preoperative MRI should be viewed asa research tool only, rather than being relied on in daily patient management. ****************** RES: Hoppe 7/99 No Reference Selected ****************** Lung/Mediastinum: Turrisi 7/99 No Reference Selected ****************** GU: Roach 7/99 No Reference Selected ****************** Radiobiology: Withers 7/99 AU: Duchesne GM, Peters LJ. TI: What is the alpha/beta ratio for prostate cancer? Rationale for hypofractionated high-dose-rate brachytherapy. SO: Int J Radiat Oncol Biol Phys 1999 Jul 1;44(4):747-8. Editor's comments: This elegant editorial concludes that hypofractionation may be the way to treat prostate cancer, based on several different lines of reasoning. This favors high dose rate afterloaded brachytherapy over permanent seed implants. It also would increase the yield from "conformal" therapy where the dose per fraction within the prostate may be greater than with "standard" treatment, giving an extra biologic boost to the higher physics dose (double-trouble for the tumor). For example, 80 Gy in 35 fractions of 2.3 Gy would be equivalent to 85 Gy in 2 Gy fractions or 89 Gy in 1.8 Gy fractions if the alpha/beta value for prostate cancer were 2.5 Gy. The argument for hypofractionated treatment for prostate cancer can also be extended with reasonable biologic confidence to any tumors whose proliferative activity is low. (Note, however, that slow growth is not always an indicator of low proliferative activity, e.g. the slow growth of the highly proliferative BCC.) The authors emphasize that in designing hypofractionated treatments it is necessary to reduce the dose to the extent necessary to avoid toxicity to the normal tissues and that this dose reduction may be substantial. A final thought is that even with "standard" treatment of prostate cancer, 2.0 Gy, rather than 1.8 Gy per fraction should be the norm. This editorial, together with the paper by Brenner and Hall (last month's journal club) should form the basis for rethinking clinical trials of prostate cancer. ****************** Brian J. Goldsmith, M.D. Moderator, IROJC From daemon Mon Jul 12 16:16:01 1999 Received: by net.bio.net (8.9.1a/8.9.1) id QAA27453; Mon, 12 Jul 1999 16:16:01 -0700 (PDT) Message-Id: <199907122316.QAA27453@net.bio.net> To: radoncjc@net.bio.net Date: Mon, 12 Jul 1999 13:05:43 -1000 Reply-To: radoncjc@net.bio.net From: Brian J Goldsmith Subject: IROJC RES 7/99 RES 7/99 was erroneously omitted from the July 1999 IROJC posting. Below is the reference, abstract, and editor comments. AU: Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, van Putten WL, Levendag PC. TI: Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. SO: Radiother Oncol 1999 Apr;51(1):35-42 Abstract: BACKGROUND AND PURPOSE: In patients with Hodgkin's disease treated by radiotherapy with a moderate total dose and a low (mean) fraction dose to the heart, the risk of ischemic heart disease was investigated during long-term follow-up. MATERIALS AND METHODS: The medical records of 258 patients treated in the period 1965-1980 with radiotherapy alone as the primary treatment were reviewed. The median follow-up was 14.2 years (range 0.7-26.2). The mean total dose and fraction dose to the heart were 37.2 Gy (SD 2.9) and 1.64 Gy (SD 0.09), respectively. The impact on the development of ischemic heart disease of treatment-related parameters, such as the applied (fraction) dose, irradiation technique (one or two fields per day), and chemotherapy in case of a relapse, was investigated. The incidence of ischemic heart disease in this patient population was compared with the expected incidence based on gender, age and calendar period-specific data for the Dutch population. RESULTS: Thirty-one patients (12%) experienced ischemic heart disease (actuarial risk at 20-25 years: 21.2% (95% C.I. 15-30). Twenty-five of them were hospitalized. When compared with the expected incidence, the relative risk (RR) of hospital admission for ischemic heart disease was 2.7 (95% C.I. 1.7-4.0). There were 12 deaths (4.7%) due to ischemic myocardial or sudden death (actuarial risk at 25 years: 10.2% (95% C.I. 5.3-19), compared to 2.3 cases that were expected to have died from these causes, yielding a standardized mortality ratio (SMR) of 5.3 (95% C.I. 2.7-9.3). Gender (male), pretreatment cardiac medical history and increasing age appeared to be the only significant factors for the development of ischemic heart disease. CONCLUSIONS: Despite the moderate total dose and the low (mean) fraction dose to the heart, the observed incidence of ischemic heart disease is high, especially after long follow-up periods. Treatment related cardiac disease in patients treated for Hodgkin's disease has only been reported for doses above 30 Gy. Although the optimum curative dose is still under debate, some studies recommend a dose as low as 32.5 Gy. The observed high rate of severe heart complications in this study advocates a dose reduction to this level, particularly in the regions where the coronary arteries are located. Editor Comments: This is not a huge series (n=258), but the patients were treated in somewhat homogeneous fashion, the total dose (mean = 37.2 Gy) and fraction size (1.64 Gy) are reasonable by today's standards, the follow-up is long (median 14.2 yrs), detailed data were available for subsequent cardiac disease, and reliable general population statistics were available. The RR for ischemic heart disease hospitalization was 2.7 and the RR for ischemic myocardial or sudden death was 5.3. Risk factors included male gender, pretreatment cardiac medical history, and increasing age. The authors conclude that we may have to get doses down to 30 Gy to see any significant drop in cardiac risk after mantle Rx.