From daemon Fri Jun 4 08:08:30 1999 Received: (from daemon@localhost) by net.bio.net (8.9.1a/8.9.1) id IAA19651; Fri, 4 Jun 1999 08:08:30 -0700 (PDT) Message-Id: <199906041508.IAA19651@net.bio.net> To: radoncjc@net.bio.net Subject: June 1999 Internet Radiation Oncology Journal Club (IROJC) Reply-To: radoncjc@net.bio.net Date: Fri, 04 Jun 1999 10:21:26 -0400 From: Brian Goldsmith June 1999 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 49th 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 6/99. (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 6/99 AU: Hoover M, Bowman LC, Crawford SE, Stack C, Donaldson JS, Grayhack JJ, Tomita T, Cohn SL. TI: Long-term outcome of patients with intraspinal neuroblastoma. SO: Med Pediatr Oncol 1999 May;32(5):353-9. Abstract: BACKGROUND: Chemotherapy, radiotherapy, and surgical decompression with laminectomy are effective therapeutic options in the treatment of cord compression from neuroblastoma (NB). We report the long-term outcome of patients with intraspinal NB treated with or without laminectomy at two large pediatric oncology centers. PROCEDURE: We reviewed the medical records and radiographs of 26 children with intraspinal NB treated at Children's Memorial Hospital in Chicago, Illinois, between 1985 and 1994 or at St. Jude Children's Research Hospital in Memphis, Tennessee, between 1967 and 1992. RESULTS: Twenty-four of the 26 patients are alive and disease-free (follow-up of 2-29 years; median, 10 years 2 months). Fifteen of the 23 patients with neurologic impairment underwent initial laminectomy. Nine of these 15 patients recovered neurologic function, including 3 patients who presented withparaplegia. Eleven of the 15 patients who underwent laminectomy have developed mild to severe spinal deformities. Eight patients with neurologic symptoms consequent to cord compression were treated with initial chemotherapy and/or surgery, but did not undergo laminectomy. Three patients with mild to moderate deficits recovered neurologic function. Four of 11 patients with intraspinal NB who did not undergo laminectomy have mild to severe scoliosis. CONCLUSIONS: A low incidence of neurologic recovery was seen in patients with long-standing severe cord compression regardless of treatment modality. For patients with partial neurologic deficits, recovery was seen in most patients following chemotherapy or surgical decompression with laminectomy. A higher incidence of spinal deformities was seen in the patients treated with initial laminectomy. Editor's comments: Mention spinal cord compression and most Radiation Oncologists automatically recommend emergency radiotherapy. One area where we can make an exception is in infants and youngsters with neuroblastoma who present with intraspinal tumor. Initial chemotherapy can relieve symptoms and result in recovery of function in the majority of children, as is well described in this series of 26 children from 2 large pediatric oncology services. Many of the resulting spinal deformities, at one time attributed to radiotherapy, are now recognized to be from the initial laminectomy. This report reminds us that long standing and severe cord compression with resultant neurologic impairment is unlikely to be reversed regardless of the initial therapy. This paper is worth reading to provide an update on the current recommended approach for infants with neuroblastoma presenting with neurologic compromise. ****************** Head/Neck/Skin: Foote 6/99 No Reference Selected ****************** GYN: Petereit 6/99 No Reference Selected ****************** GI / Soft Tissue Sarcoma: Tepper 6/99 No Reference Selected ****************** CNS: Bauman 6/99 AU: Mandell LR, Kadota R, Freeman C, Douglass EC, Fontanesi J, Cohen ME, Kovnar E, Burger P, Sanford RA, Kepner J, Friedman H, Kun LE. TI: There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. SO: Int J Radiat Oncol Biol Phys 1999 Mar 15;43(5):959-64. Abstract: PURPOSE: In June 1992, POG began accrual to a phase III study, POG-9239, designed to compare the time to disease progression, overall survival, and toxicities observed in children with newly diagnosed brainstem tumor treated with 100 mg/m2 of infusional cisplatin and randomized to either conventional vs. hyperfractionated radiotherapy. METHODS AND MATERIALS: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the pons. Histologic confirmation of diagnosis was not mandatory, provided that the clinical and MRI scan findings were typical for a diffusely infiltrating pontine lesion. Treatment consisted of a six-week course of local field radiotherapy with either once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy (arm 1) or a twice a day regimen of 117 cGy per fraction to a total dose of 7020 cGy (the second of the three hyperfractionated dose escalation levels of POG-8495) (arm 2). Because of previously reported poor results with conventional radiotherapy alone, cisplatin was included as a potential radiosensitizer in an attempt to improve progression-free and ultimate survival rates. Based on results of the phase I cisplatin dose escalation trial, POG-9139, 100 mg/m2 was chosen for this trial and was delivered by continuous infusion over a 120-hour period, beginning on the first day of radiotherapy and repeated during weeks 3 and 5. One hundred thirty eligible patients were treated on protocol, 66 on arm 1 and 64 on arm 2. RESULTS: The results we report are from time of diagnosis through October 1997. For patients treated on arm 1, the median time to disease progression (defined as time to off study) was 6 months (range 2-15 months) and the median time to death 8.5 months (range 3-24 months); survival at 1 year was 30.9% and at 2 years, 7.1%. For patients treated on arm 2, the corresponding values were 5 months (range 1-12 months) and 8 months (range 1-23 months), with 1- and 2-year survival rates at 27.0% and 6.7%, respectively. Evaluation of response by MRI at 4 or 8 wks post treatment was available in 108 patients and revealed a complete responsein 1 patient of each Rx arm, a partial response (greater than 50% decrease in size) in 18 patients of arm 1 and 15 patients of arm 2, minimal to no response (stable) in 25 patients of arm 1 and 23 patients of arm 2, and progressive disease in 13 patients of arm 1 and 12 patients of arm 2. The pattern of failure was local in all patients. Morbidity of treatment was similar in both Rx arms, with no significant toxicity (including hearing loss) reported. Autopsy was performed in 6 patients, and confirmed the presence of extensive residual tumor in these cases. CONCLUSION: The major conclusion from this trial is that the hyperfractionated method of Rx 2 did not improve event-free survival (p equals 0.96) nor did it improve survival (p equals 0.65) over that of the conventional fractionation regimen of Rx 1, and that both treatments are associated with a poor disease-free and survival outcome. Editor's comments: This article, in conjuntion with the editorial by Drs. Fisher and Donaldson in the same issue and a recent excellent review article by Drs. Farmer and Freeman (IJROBP 40(2), 265-271,1998) summarize the standard of treatment for pediatric patients with brainstem gliomas. Unfortunately, the standard of treatment leaves much to be desired as the evidenced by the short median survivals (8 months) and low 2 year survivorship (7%) with conventionally fractionated radiotherapy alone. Drs. Fisher and Donaldson in their editorial state "In cooperative group trials of the next millenium, we need to pursue entirely new approaches to these tumors, perhaps even beyond those such as chemosensitization, local-reginal therapies, cell signalling agents, angiogenesis inhibitors, and gene therapies". Hopefully, the oncology community will rise to this challenge as new approaches to this dreadful disease are sorely needed. With this issue, I have assumed editorship of the CNS component of the Internet Journal Club. I would like to thank my predecessor, Dr. David Larson for his editorship of this section for the past 4 years. I hope I will be able to supply a similarly diverse and engaging selection of references as provided by Dr. Larson in the past. ****************** Physics/Dosimetry: Purdy 6/99 No Reference Selected ****************** Breast: Recht 6/99 AU: Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS, Shriver C, Feldman S, Kusminsky R, Gadd M, Kuhn J, Harlow S, Beitsch P. TI: The sentinel node in breast cancer--a multicenter validation study. SO: N Engl J Med 1998 Oct 1;339(14):941-6 URL: http://www.nejm.org/content/1998/0339/0014/0941.asp Abstract: BACKGROUND: Pilot studies indicate that probe-guided resection of radioactive sentinel nodes (the first nodes that receive drainage from tumors) can identify regional metastases in patients with breast cancer. To confirm this finding, we conducted a multicenter study of the method as used by 11 surgeons in a variety of practice settings. METHODS: We enrolled 443 patients with breast cancer. The technique involved the injection of 4 ml of technetium-99m sulfur colloid (1 mCi [37 MBq]) into the breast around the tumor or biopsy cavity. "Hot spots" representing underlying sentinel nodes were identified with a gamma probe. Sentinel nodes subjacent to hot spots were removed. All patients underwent a complete axillary lymphadenectomy. RESULTS: The overall rate of identification of hot spots was 93 percent (in 413 of 443 patients). The pathological status of the sentinel nodes was compared with that of the remaining axillary nodes. The accuracy of the sentinel nodes with respect to the positive or negative status of the axillary nodes was 97 percent (392 of 405); the specificity of the method was 100 percent, the positive predictive value was 100 percent, the negative predictive value was 96 percent (291 of 304), and the sensitivity was 89 percent (101 of 114). The sentinel nodes were outside the axilla in 8 percent of cases and outside of level 1 nodes in 11 percent of cases. Three percent of positive sentinel nodes were in nonaxillary locations. CONCLUSIONS: Biopsy of sentinel nodes can predict the presence or absence of axillary-node metastases in patients with breast cancer. However, the procedure can be technically challenging, and the success rate varies according to the surgeon and the characteristics of the patient. Editor's comments: This multi-instutional study was performed to show that sentinal node biopsy (SNB) could be performed reliably by a large number of surgeons. It was successful in doing so, laying the groundwork for the recently-opened NSABP B-32 trial. In this study, patients are randomly assigned to conventional axillary dissection or SNB. Patients with positive nodes on SNB by conventional light-microscopic staining go on to axillary dissection. One of the questions this trial will answer is the risk of axillary nodal recurrence in patients with a "negative" SNB. It is important to note that the false-negative rate of SNB in the published series has been from 2-8% approximately. However, since the Level I and a portion of Level II of the axilla are included in tangential fields, the risk of clinical failure may be substantially lower. Another recently-opened trial, the American College of Surgeons trial Z0011, randomizes patients with positive SNB to axillary dissection or observation; it specifically prohibits the use of axillary or supraclavicular fields. There are no data on what the risk of regional nodal failure in such patients is. Whether patients will be willing to participate in such a trial remains to be seen. ****************** RES: Hoppe 6/99 No Reference Selected ****************** Lung/Mediastinum: Turrisi 6/99 AU: Baldini EH, DeCamp MM Jr, Katz MS, Berman SM, Swanson SJ, Mentzer SJ, Bueno R, Sugarbaker DJ. TI: Patterns of recurrence and outcome for patients with clinical stage II non-small-cell lung cancer. SO: Am J Clin Oncol 1999 Feb;22(1):8-14. Abstract: Forty-six patients with pathologic clinical stage II non-small-cell lung carcinoma underwent resection with or without adjuvant radiotherapy from 1989 through 1994. These patients were analyzed to determine patterns of recurrence and survival. Surgery consisted of pneumonectomy for 11 patients, bilobectomy for two patients, lobectomy for 29 patients, and wedge or segmental resection for four patients. Adjuvant radiotherapy was delivered to 29 patients, and the median total dose was 54 Gy (range, 44-60 Gy). Median follow-up time was 23 months for all patients and 25 months for surviving patients. Twenty-six of 46 patients have had recurrence. The site of first recurrence was locoregional for 9 of 46 patients (20%) and distant for 17 of 46 patients (37%). The median time to locoregional recurrence was 18 months for patients treated with radiotherapy and 13 months for patients treated without radiotherapy. An isolated locoregional recurrence (with no simultaneous distant recurrence) was seen in 2 of 28 evaluable patients (7%) treated with radiotherapy compared with 3 of 17 patients (18%) not treated with radiotherapy. For all patients, the 3-year disease-free survival rate was 52%, and the overall survival rate was 52%. Among patients treated with radiotherapy, the 3-year disease-free survival and overall survival rates were 56% and 56%, respectively, compared with 46% and 43%, respectively, for patients who did not receive radiotherapy (p values were not significant). The locoregional recurrence rate was 33% for patients with adenocarcinoma and 15% for those with squamous cell carcinoma. The distant recurrence rates by histologic characteristic were 56% and 20%, respectively. For patients with clinical stage II non-small-cell lung cancer, postoperative radiotherapy appears to improve locoregional control. However, the preponderance of recurrences remains distant. Further study is warranted with special emphasis on control of systemic disease. Editor's comments: This is a brief paper that adds another log to the fire on post-operative therapy in lung cancer. The title is really incorrect because it looks at 46 cases of pathologically proven, post-operative lung cancer. It suggests a very modest improvement in local control, but if confidence intervals were done, I am sure that they would overlap. Local recurrence was 18% and 24% for treated and observed patients. Importantly, the isolated local relapse, defined as being in the hilum or adjacent mediastinum, not the lung parenchyma or supraclavicular area was 2/28 (7%) when receiving post operative radiotherapy versus 3/17 (18%) if not treatment was offered. Three year survival was 56% and 46% respectively for radiotherapy and observation groups. At the recent ASCO meeting, the long awaited intergroup trial, ECOG 3590 was reported. It compared cisplatin-etoposide plus radiotherapy concurrently to radiotherapy by itself in 351 patients. The median survival was 41 months for radiotherapy alone and 39 months when chemotherapy was added. Local failure and patterns of failure in this study of stage II and III patients was not yet available. Only two-thirds received the entire 4 cycles of chemotherapy and three-quarters received the intended radiotherapy. Far and away, the most important site of failure is distant disease. The hope that newer chemotherapy regimens will influence this is currently being addressed with many continental Europe studies using chemotherapy alone versus observation (+/- thoracic radiotherapy in some cases) -- Mito/vind/cisplatin; vinorelbine, and cisplatin plus any other drug make up the bulk of the drugs used. In Canada, the BR-10 trial, vinorelbine/cisplatin is to be used in Stage II patients versus a no treatment control arm. This is open in many US centers as well, and all of the cooperative groups. The CALGB presently offers a trial of 4 cycles of Carboplatin/paclitaxel, and randomizes those completing 4 cycles to post operative radiotherapy or observation. Post op therapy remains controversial in light of the PORT trial discussed here last summer. The mortality of the trials in that meta-analysis has not been seen in the Baldini paper, which nicely details pre-operative stage, mediastinoscopy work-up, and surgical procedures, or in the ECOG managed intergroup trial. But PORT treated early patients to higher dose with broad volumes and older equipment. Despite the glimmer of light about improved local control, we remain largely in the dark about real benefit for post operative therapy in proven stage II disease. Clearly judicious dose and volumes should be used in patients selected for this therapy. The Baldini paper is carefully written, clear about patients selected for the review and for the treatment, and interesting about the changes in clinical to pathological stage. All trial at this time leave open the merit of post-operative treatment versus treating those as they fail with isolated failures and sparing those who are destined to not fail, or who will fail predominantly with distant disease. The controversy continues. ****************** GU: Roach 6/99 No Reference Selected ****************** Radiobiology: Withers 6/99 AU: Trott K-R, Shirazi A, Heasman F. TI: Modulation of accelerated repopulation in mouse skin during daily irradiation. SO: Radiother Oncol 50:261-266, 1999. Abstract: BACKGROUND AND PURPOSE: The timing of acceleration of repopulation in the epidermis during daily irradiation is related to the development of skin erythema and epidermal hypoplasia. Therefore, the relationship between impairment of the epidermal barrier function, the dermal inflammatory response and epidermal hypoplasia with the acceleration of repopulation was investigated. MATERIALS AND METHODS: Skin fields of approximately 1 cm2 on the thighs of TUC mice were given five daily fractions of 3 Gy in each week followed by top-up doses at the end of the first, the second, or the third week to determine residual epidermal tolerance and to calculate repopulation rates in weeks 1, 2, or 3. Systemic modulation of repopulation was attempted by daily indomethacine during fractionated irradiation whereas tape stripping or UV-B exposure before the start of fractionated irradiation attempted local modulation. In parallel experiments, the water permeability coefficient of the epidermis was determined ex vivo by studying transepidermal transport of tritiated water. RESULTS: Without modulation, no repopulation was found in the first week of daily fractionation but repopulation compensated 30% of the dose given in week two and 70% of the dose given in week three. Only tape stripping before the start of fractionated irradiation accelerated repopulation in week one. UV-B had no effect on repopulation although it stimulated proliferation as much as tape stripping. Indomethacin did not suppress acceleration of repopulation. A significant increase in transepidermal water loss was found but only after repopulation had already accelerated. CONCLUSIONS: Acceleration of repopulation in mouse epidermis during daily-fractionated irradiation is not related to the simultaneous development of an inflammatory response. Also, the loss of the epidermal barrier function is not involved in the development of the acceleration response, which rather seems to be triggered directly by the decreased cellularity of the epidermis. Editor's comments: This paper is a useful addition since the authors provide data to support the commonly-presumed, but not rigorously tested hypothesis that the major determinant of a homeostatic repopulation response is the decreased density of the relevant cell population (in this case, the skin epithelium). They rule out inflammation or transudation as factors. Experiments in which the differentiated functional keratinocytes are stripped off the surface suggest that depletion of functional keratinocytes will trigger repopulation. It seems reasonable to conclude that hemopoiesis also is a systemic feedback response to differentiated cell depletion (via erythropoietin) but experiments with conventional and specific pathogen-free mice suggest that loss of clonogenic cells from the jejunal crypt in the absence of much depletion of functional cells on the villus will also provoke homeostatic regeneration. In summary, reduced cell density is the likely cause of a repopulation response but the cells whose depletion is critical may be from either the clonogenic or the differentiated subpopulation, or both. ****************** Brian J. Goldsmith, M.D. Moderator, IROJC