From owner-radoncjc@net.bio.net Wed Dec 6 01:43:42 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id C1C5717BA4; Wed, 6 Dec 2000 01:43:29 +0000 (GMT) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 6028) id EF61A17ABD; Wed, 6 Dec 2000 01:43:23 +0000 (GMT) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 6024) id 4D56717BA4; Wed, 6 Dec 2000 01:34:55 +0000 (GMT) Received: from mail1.radiological.com (mail1.radiological.com [206.13.127.226]) by mercury.hgmp.mrc.ac.uk (Postfix) with SMTP id 99C4E415E2 for ; Wed, 6 Dec 2000 01:34:41 +0000 (GMT) Received: from RASROUTING-Message_Server by mail1.radiological.com with Novell_GroupWise; Tue, 05 Dec 2000 17:34:20 -0800 Message-Id: X-Mailer: Novell GroupWise 5.5.4 From: "Brian Goldsmith MD" To: Subject: December 2000 Internet Radiation Oncology Journal Club (IROJC) Content-Disposition: inline Newsgroups: bionet.radoncjc Date: Wed, 6 Dec 2000 01:43:23 +0000 (GMT) Sender: owner-radoncjc@net.bio.net Precedence: bulk December 2000 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 67th collection of references suggested for attention and discussion by the IROJC's Board of Editors: Sarah Donaldson, M.D. Editor, Pediatric Radiation Oncology Robert Foote, M.D. Editor, Head and Neck / Skin Radiation Oncology Abram Recht, M.D. Editor, Breast Radiation Oncology Rich Hoppe, M.D. Editor, Reticuloendothelial System Radiation Oncology Dan Petereit, M.D. Editor, Gynecological Radiation Oncology Andrew Turrisi, M.D. Editor, Lung and Mediastinum Radiation Oncology Joel Tepper, M.D. Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology Mack Roach, M.D. Editor, Genitourinary Radiation Oncology Glenn Bauman, M.D. Editor, Central Nervous System Radiation Oncology Rod Withers, M.D., D.Sc. Editor, Radiobiology James Hayman, M.D. Editor, Health Services Research George Chen, Ph.D. Editor, Radiation Biophysics ----------------------------------------------------- You're encouraged to critically review this set of references and respond by posting your comments to the IROJC readership at radoncjc@net.bio.net. ----------------------------------------------------- Peds: Donaldson 12/00 AU: Cotterill SJ, Ahrens S, Paulussen M, Jurgens HF, Voute PA, Gadner H, Craft AW. TI: Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. SO: J Clin Oncol. 2000 Sep;18(17):3108-14. URL: http://www.jco.org/cgi/content/full/18/17/3108 ID: PMID: 10963639 UI: 20420055 Abstract: PURPOSE: To further elaborate on prognostic factors for Ewing's sarcoma of bone and to document improvements in relapse-free survival (RFS) and trends in local therapy over the study period (1977 to 1993). PATIENTS AND METHODS: A retrospective analysis was performed on a combined Gesellschaft Fur Padiatrische Onkologie und Hamatologie/Cooperative Ewing Sarcoma Study and United Kingdom Children's Cancer Study Group/Medical Research Council data set of 975 patients registered with the respective trial offices before the current collaborative European Intergroup Cooperative Ewing's Sarcoma Study trial. Both groups independently undertook studies with similar chemotherapy during the period. RESULTS: The key adverse prognostic factor is metastases at diagnosis (5-year RFS, 22% of patients with metastases at diagnosis v 55% of patients without metastases at diagnosis; P: <.0001). For the group with metastases, there was a trend for better survival for those with lung involvement compared with those with bone metastases or a combination of lung and bone metastases (P: <.0001). In the group of patients with no metastases at diagnosis, multivariate analysis demonstrated that site (axial v other), age-group (< 15 v > or = 15 years), and period of diagnosis had significant influence on RFS (all P: <.005). RFS was superior in the period after 1985 compared with the period before 1985 for nonmetastatic patients (45% v 60%, respectively; P: <.0001) and for metastatic patients (16% v 30%, respectively; P: =.016). Patients who relapsed within 2 years of diagnosis had a less favorable prognosis than patients who relapsed later (5-year survival after relapse, 4% v 23%, respectively; P: <.0001). There were other changes over the period; in particular, radiotherapy or amputation were more common in the period before 1986, whereas endoprosthetic surgery was widely used in the later period. CONCLUSION: Survival and RFS improved over the period. Prognostic factors are metastases at diagnosis, primary site, and age. Editor's comments: This article represents data on a large number of patients, from several excellent centers, and adds to our understanding of prognostic factors in Ewing's Sarcoma. The favorable prognostic factors have been identified in other large studies, but confirmed here. It is important to recognize that patients with metastatic disease continue to have only a 22% 5-yr RFS, despite ever increasingly aggressive chemotherapy. Those with pulmonary metastases only fair better than those with bone metastases. Although outcome for patients with Ewing's sarcoma seems improved, we still have a long way to go! ****************** Head/Neck/Skin: Foote 12/00 No Reference Selected ****************** Breast: Recht 12/00 AU: Olson JA Jr, Morris EA, Van Zee KJ, Linehan DC, Borgen PI. TI: Magnetic resonance imaging facilitates breast conservation for occult breast cancer. SO: Ann Surg Oncol. 2000 Jul;7(6):411-5. ID: PMID: 10894136 UI: 20350634 Abstract: INTRODUCTION: Occult primary breast cancer, i.e., isolated axillary adenocarcinoma without detectable tumor in the breast by either physical exam or mammography, represents up to 1% of operable breast cancer. Modified radical mastectomy (MRM) is generally the accepted treatment for this condition although tumor is identified in only two-thirds of mastectomy specimens. Breast magnetic resonance imaging (MRI) can identify occult breast carcinoma and may direct therapy. This study examined the ability of breast MRI to detect occult breast cancer and to facilitate breast conservation therapy. METHODS: Forty women with biopsy-proven metastatic adenocarcinoma to an axillary lymph node and no evidence of primary cancer were studied. All patients had a physical examination, mammography, and MRI of the breast. Using a dedicated breast coil, MRI imaging was performed with and without gadolinium enhancement. Positive MRI scans were compared with histopathologic findings at the time of operation (n = 21). RESULTS: MRI identified the primary breast lesion in 28 of 40 women (70%). Of these 28 patients, 11 had MRM, 11 had lumpectomy/axillary lymph node dissection (ALND)/radiotherapy (XRT), 2 had ALND/XRT alone, and 4 had no local treatment secondary to stage IV disease. Two women initially treated with lumpectomy/ALND subsequently had mastectomy for positive margins. Of the women with positive MRI who had breast surgery, 21 of 22 (95%) had tumor within the surgical specimen. Twelve women had negative MRI of the breast. Five of these 12 underwent MRM, of whom 4 had no tumor in the mastectomy specimen. The remaining 7 patients had ALND and whole breast radiation (ALND/XRT) (n = 5), or were observed (n = 2). Overall, 18 of 34 women surgically treated had MRM, while 16 (47%) preserved their breast. Tumor yield for patients having breast surgery was 81%. CONCLUSIONS: MRI of the breast can identify occult breast cancer in many patients and may facilitate breast conservation in select women. Negative breast MRI predicts low tumor yield at mastectomy. Editor's comments: This important article from the group at Memorial Sloan-Kettering Cancer Center is the largest I know of examining the role of MRI in searching for "occult" breast lesions in patients presenting with axillary adenopathy with no apparent primary source on conventional physical examination and mammography. MRI was able to find a primary in 70% of the studied women. The false-negative rate in patients undergoing mastectomy was 1 of 5 patients, but this was in someone who had a technically inadequate MRI. Thus, MRI appears to be a powerful tool for evaluating such patients. Of interest, 7 patients who had negative MRIs underwent axillary dissection but not breast surgery (5 had breast RT and 2 had observation of the breast). There were no local failures in this group, but the median follow-up for them was only 19 months. Prior studies of "blind" breast irradiation in such patients without known primaries have shown long-term local failure rates of 20-25%. Hence, it will be very interesting to see how this patient group in the current series does with further observation. At present, my own policy remains to recommend mastectomy for those individuals where a breast primary cannot be discovered by palpation or imaging studies. ****************** RES: Hoppe 12/00 AU: Schlembach PJ, Wilder RB, Tucker SL, Ha CS, Rodriguez MA, Hess MA, Cabanillas FF, Cox JD. TI: Impact of involved field radiotherapy after CHOP-based chemotherapy on stage III-IV, intermediate grade and large-cell immunoblastic lymphomas. SO: Int J Radiat Oncol Biol Phys. 2000 Nov 1;48(4):1107-10. URL: http://hub.elsevier.com/pii/S0360301600007604 ID: PMID: 11072169 UI: 20525663 Abstract: Purpose: To analyze the impact of involved field radiotherapy on local control, freedom from progression, and overall survival in patients with clinical Stage III-IV, intermediate grade, or large-cell immunoblastic lymphomas that responded to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based induction chemotherapy. Methods and Materials: From July 1989 through October 1996, 32 patients with clinical Stage III and 27 patients with clinical Stage IV, intermediate grade, or large-cell immunoblastic lymphomas were prospectively enrolled on two protocols at The University of Texas M. D. Anderson Cancer Center. None had previously undergone treatment for lymphoma. The median patient age was 54 years (range: 26-85 years). There were a total of 172 involved sites of disease at presentation. All 59 patients received CHOP-based chemotherapy. At least six cycles of chemotherapy were delivered to 92% of the patients. Involved field radiotherapy (39.6-40.0 Gy in 20-22 fractions in 74% of cases) was administered to 28/59 (47%) patients beginning 3-4 weeks after chemotherapy. Sites were irradiated at the discretion of the treating physician. Irradiated and nonirradiated groups were compared in terms of maximum pre-chemotherapy tumor size and University of Texas M. D. Anderson Cancer Center tumor score. Kaplan-Meier estimates of local control per patient, freedom from progression, and overall survival for the irradiated and nonirradiated groups were calculated in terms of the stage of disease and treatment delivered. The resulting curves were compared using the log-rank test. The Cox proportional hazards model was used to assess the prognostic significance of tumor size, tumor score, treatment delivered, and stage. Results: The median length of follow-up for all patients was 53 months (range: 4-96 months). The median tumor size at the start of chemotherapy in irradiated patients was 4.5 cm (range: 0-15 cm) versus 3 cm (range: 0-7 cm) in nonirradiated patients (p = 0.004). The irradiated and nonirradiated groups were not significantly different in terms of tumor scores. Radiotherapy improved (p = 0.001) local control (5-year rates: 89% versus 52%) for Stages III and IV combined. This benefit was due to the dramatic improvement (p = 0.0009) in local control for patients with lymphomas measuring >/=4 cm at the start of chemotherapy (5-year rates: 89% for irradiated patients versus 33% for nonirradiated patients). Radiotherapy also improved (p = 0.003) freedom from progression (5-year rates: 85% for irradiated patients versus 51% for nonirradiated patients) for Stages III and IV combined. On multivariate analysis, radiotherapy was the most significant factor affecting local control and freedom from progression. Overall survival was not significantly different (p = 0. 620) between irradiated and nonirradiated patients (5-year rates: 87% versus 81%, respectively). When Stages III and IV were analyzed separately, radiotherapy improved local control and freedom from progression but not overall survival. Radiotherapy was tolerated reasonably well, with the main toxicity being moderate myelosuppression. Eleven out of 12 (92%) patients with recurrent disease at the time of their last follow-up visit were treated initially with chemotherapy alone. Conclusion: Involved field radiotherapy improved local control and freedom from progression in patients with >/=4 cm Stage III-IV, intermediate grade, or large-cell immunoblastic lymphomas that responded to CHOP-based induction chemotherapy. Involved field radiotherapy was tolerated reasonably well. Editor's comments: Although the advantage of combined modality therapy over chemotherapy alone has been demonstrated clearly for stage I-II diffuse large cell lymphoma in randomized trials of the SWOG and ECOG (see June 1995 and August 1998 Internet Radiation Oncology Journal Clubs), the role of radiation therapy in stage III-IV disease has not been demonstrated convincingly. This report looks retrospectively at the MD Anderson data for stage III-IV and shows a significant improvement in local control and freedom from progression for patients treated with combined modality therapy vs. chemotherapy alone. There was no apparent improvement in survival, but longer term follow up may show some differences. Of course this paper suffers from all of the problems of a retrospective review, but it lends a bit more support to the use of radiation therapy in this setting. The authors refer to the few randomized series that exist (Aviles et al., and O'Connell et al.) that support the same notion. In addition, there are data that indicate that patients with advanced disease often relapse in site of initial involvement (Shipp et al.). From the radiation oncologist's perspective, an excellent randomized clinical trial could be designed to answer the question. However, unless radiation oncologists become more involved in the lymphoma trials of cooperative clinical trials groups, it is likely that trials for these patients will continue to emphasize the use of systemic therapies, including stem cell transplantation and monoclonal antibodies. ****************** GYN: Petereit 12/00 AU: Smith RS; Kapp DS; Chen Q; Teng NN. TI: Treatment of high-risk uterine cancer with whole abdominopelvic radiation therapy. SO: Int J Radiat Oncol Biol Phys 2000 Oct 1;48(3):767-78. URL: http://hub.elsevier.com/pii/S0360301600007240 ID: PMID: 11020574 UI: 20476648 Abstract: Purpose: To evaluate the treatment outcomes in patients with optimally debulked Stage III and IV endometrial adenocarcinoma (ACA) or Stages I-IV uterine papillary serous (UPSC) or clear cell (CCC) carcinoma of the uterus, treated postoperatively with whole abdominopelvic irradiation (WAPI). Methods and Materials: Between 1979 and 1998, 48 patients received postoperative WAPI at our institution. Twenty-two patients had FIGO Stage III or Stage IV ACA and 26 patients had FIGO Stages I-IV UPSC or CCC. The median dose was 30 Gy to the upper abdomen and 49.8 Gy to the pelvis. Mean follow-up was 37 months (2.4-135 months). Results: The 3-year estimated disease-free survival (DFS) and overall survival (OS) rates for the entire group were 60% and 77%, respectively. Patients with ACA had 3-year DFS and OS of 79% and 89%, respectively, compared with 47% and 68% in the UPSC/CCC group. Early-stage patients (I and II) with UPSC/CCC had 3-year DFS and OS of 87% compared with 32% and 61% in those with advanced (Stage III and IV) disease. The 3-year actuarial major complication rate was 7%, with no treatment-related deaths. All 4 failures in the ACA group were extra-abdominal and 6 of the 11 in the UPSC/CCC group had an extra-abdominal component. Age and UPSC/CCC histology were significant prognostic factors for DFS and OS. In addition, stage and number of extrauterine sites of disease were significant predictors for DFS in UPSC/CCC. Conclusion: WAPI is a safe, effective treatment for patients with optimally debulked advanced-stage uterine ACA or early-stage UPSC/CCC. Survival was significantly worse in advanced-stage UPSC/CCC patients. We recommend future trials of WAPI with concurrent, or subsequent systemic therapy in patients with advanced-stage UPSC or CCC. Editor's comments: Smith et al. reported the Stanford Experience using whole abdominal radiotherapy (WAR) in the management of patients with high-risk endometrial cancer. Two groups of patients were retrospectively investigated: 1) stage III and IV adenocarcinomas and stages I-IV uterine papillary serous (USPC) or clear cell carcinomas (CCC). All patients had thorough surgical staging with an assessment of the pelvic and para-aortic in 83% of the patients. The technique of WAR was 30 to the whole abdomen in 1.2 to 1.5 Gy/fx followed by a 20 Gy pelvic boost. About 19% of the patients had the para-aortic lymph nodes boosted. Half of the patients received a vaginal brachytherapy boost with either LDR or HDR. A small percentage of the patients were treated with either chemotherapy and/or hormonal therapy. The 3-year DFS was quite good at 79% for the stage III adenocarcinomas patients, and 87% for the stage I/II USPC and CCC patients. As expected, stage III/IV USPC and CCC experienced the lowest DFS of 32%. The significant actuarial complication rate was 7% (grade 3, 4). The risk of extra-abdominal failures were higher in the USPC/CCC cohorts compared the stage III patients with adenocarcinomas. This study represents another retrospective series that add credibility to the efficacy of whole abdominal radiotherapy for high-risk endometrial patients. The authors nicely summarize the results from other retrospective series. The improved outcome for patients in this series compared to others may be a reflection of thorough surgical staging, and possibly patient selection. As outlined in their discussion, two important GOG trials have been completed which address the issue of WAR: GOG 94 - a phase II study of WAR for stage III patients with adenocarcinomas and all stages of USPC/CCC that have been completely debulked; and GOG 122 - a phase III study comparing WAR to platinum based chemotherapy. GOG 94 reported similar 3-year survival rates of 33% for both stage III/IV adenocarcinoma and stage III/IV clear cell and papillary serous patients. The vaginal recurrence rates were 4.2%. GOG 122 completed accrual of 387 patients in February of this year. Rumor has it [you did not hear it from me!], that the WAR patients might be doing slightly better. The final results of both studies are eagerly anticipated. A very interesting study was presented this year at ASTRO by Mundt et al.(1) They reported a 50% pelvic failure rate for stage III/IV endometrial patients who underwent complete surgical debulking followed by 4 to 6 cycles of chemotherapy. This study emphasizes that local control should not be minimized as attempts are made to achieve distant control. Finally, a word on patient selection and technique when using WAR. Eligible patients for WAR include those that are medically fit, have been optimally debulked (< 1 cm) and have a significant risk for upper abdominal failure. When discussing these patients at tumor board it needs to be emphasized that chemotherapy response rates for endometrial patients are much lower when compared to ovarian patients with similar stages of disease - especially clear cell patients (response rates of only 25 to 30%). Regarding technique, I usually deliver 25.2 Gy at 1.2 Gy per fraction AP-PA, using posterior renal blocks only, no hepatic blocks, a small AP-PA cardiac block, and an AP-PA femoral neck block, not head, with the patient supine. Also, at the time of simulation it is critical to observe the patients breathing in order to cover the diaphragm. It is helpful to perform an IVP at the time of simulation, and to confirm critical organ location with a planning CT. For the pelvic boost, I re-simulate the patient prone with some type of bowel immobilization device, and deliver an additional 20 to 25 Gy at 1.8 Gy fraction. I do believe it is important to treat the entire vagina including a vaginal boost to a 20 Gy LDR equivalent, using either LDR or HDR for the USPC patients. I would also recommend boosting the vaginal apex for patients with cervical involvement. Finally, these patients all experience significant nausea due to massive serotonin release. Therefore, prophylactic anti-emetics are indicated. I often start compazine or zofran 2 to 3 days prior to initiating radiation. If you forget, your patients will be calling you 2 hours after their first treatment! 1. Mundt AJ, McBride RB, Connell PP. Pelvic recurrence in high-risk pathologic stage I-IV endometrial carcinoma patients following adjuvant chemotherapy alone: implications for locoregional radiation therapy. International Journal of Radiation Oncology, Biology and Physics. ASTRO 2000 (Abstract #27). ****************** Lung/Mediastinum: Turrisi 12/00 AU: Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, Perry MC, Livingston RB, Johnson DH. TI: A Randomized Trial of Postoperative Adjuvant Therapy in Patients with Completely Resected Stage II or IIIa Non-Small-Cell Lung Cancer. SO: N Engl J Med. 2000 Oct 26;343(17):1217-1222. URL: http://www.nejm.org/content/2000/0343/0017/1217.asp ID: PMID: 11071672 UI: No Cit. ID assigned Abstract: Background: We conducted a randomized trial to determine whether combination chemotherapy plus thoracic radiotherapy is superior to thoracic radiotherapy alone in prolonging survival and preventing local recurrence in patients with completely resected stage II or IIIa non-small-cell lung cancer. Methods: After surgical staging and resection of the tumor (usually by lobectomy or pneumonectomy), the patients were randomly assigned to receive either four 28-day cycles of cisplatin (60 mg per square meter of body-surface area intravenously on day 1) and etoposide (120 mg per square meter intravenously on days 1, 2, and 3) administered concurrently with radiotherapy (a total of 50.4 Gy, given in 28 daily fractions) or radiotherapy alone (a total of 50.4 Gy, given in 28 daily fractions). Results: Of the 488 patients who were enrolled in the study, 242 were assigned to receive radiotherapy alone and 246 were assigned to receive chemotherapy and radiotherapy. The median duration of follow-up was 44 months. Treatment-associated mortality was 1.2 percent in the group given radiotherapy alone and 1.6 percent in the group given chemotherapy and radiotherapy. The median survival was 39 months in the group given radiotherapy and 38 months in the group given chemotherapy and radiotherapy (P= 0.56 by the log-rank test). The relative likelihood of survival among patients assigned to receive chemotherapy and radiotherapy, as compared with those assigned to receive radiotherapy alone, was 0.93 (95 percent confidence interval, 0.74 to 1.18). Intrathoracic disease recurred within the radiation field in 30 of 234 patients (13 percent) in the group given radiotherapy and in 28 of 236 patients (12 percent) in the group given chemotherapy and radiotherapy (P=0.84); data on recurrence were not available for 18 patients. Conclusions: As compared with radiotherapy alone, adjuvant radiotherapy and chemotherapy with cisplatin and etoposide does not decrease the risk of intrathoracic recurrence or prolong survival in patients with completely resected stage II or IIIa non-small-cell lung cancer. Editor's comments: This celebrated paper has been widely presented (ASTRO 1999, ASCO 2000, IASLC, Tokyo 2000) and now the New England Journal. As ASTRO's first Plenary Session selection, I was asked to comment on it and took the perspective of the role of post operative adjuvant therapy. The paper reports on the lack of benefit in survival to the addition of cisplatin etoposide to post operative radiotherapy (MST 38 mos. + chemo; 39 mos. - chemo) The toxicity is underscored and significant with the addition of concurrent radiotherapy, particularly myelosuppression and esophagitis. The paper and the Tokyo analysis highlights that the stratification variables, multiple versus single and dissection versus sampling were highly statistically significant predictors of survival and time to recurrence. Age, non-squamous histology and gender were all associated with adverse hazard ratios -- only gender was marginal, the others significant. This adds very little to the controversy of what to do with post op N-1 and N-2 patients. One can continue to argue that post operative radiotherapy reduces local failure for squamous patients with N-2, but there is no prospective data clearly indicating this in non-squamous. Since the current report shows the degree of dissection and level of nodes are of major importance, these variables need control in future studies and are not completely controlled in the reports of benefit. The issue of benefit in N-1 patients seems completely opaque to me, and the PORT trial looms as strong evidence for not doing it. The risk of complication and mortality may be dose, technique and volume related, but there is not a glimmer of evidence suggesting benefit in local or overall survival in N-1 patients. This year at ASTRO, a symposium was held that dismantled aspects, one by one of the PORT meta-analysis. Unfortunately, the PORT trialists were not included in the debate, which was more an impassioned mugging than a scientific discourse. One can surely mount evidence that the PORT trials are flawed, and the methodology was lacking, but there remains no positive assertions of benefit in prospective data. If this is such a good idea, why cannot we use prospective data to prove it? None exists right now, and the feverish and shrill pitch of the argument leads me to hang my head. Why not design, mount and contribute to trials rather than degrade published research? Post operative radiotherapy is not on terra firma. It is NOT indicated in N-0. It needs to be considered unproven and potentially hazardous in N-1. It might increase local control in N-2 disease, but I'd not bet the farm on this. The Keller paper also reports failure pattern. It shows local failure to be between 20 and 25% with or without chemotherapy, and there is no significant difference. There is perhaps a slight trend favoring reduced systemic failure with the chemotherapy used. Together with the toxicity data, this leads me to distinguish this from emerging results in bulky disease. There concurrent therapy seems to be emerging as better based on the Furuse report from JCO 9/99 (previously reviewed here) and two oral reports about RTOG 9410. On the other hand, post-operative therapy represents a frail population, more prone to distant disease and more hampered by toxicity -- do we need concurrent therapy here or does that actually force us to use less effective chemotherapy? Do we need to restrict enrollment or at least control for dissection type, sampling or complete? I think sequential therapy with two to three cycles followed by limited volume radiotherapy constitutes our best trial approach. Until we have these facts, treating N-2+ patients with NSCLC, particularly non-squamous cases, with post op radiotherapy seems relatively weakly indicated by evidence, and there remain substantial risks if immoderate doses and volumes are used. Harangues for or against post op or the PORT trial will not change this -- evidence or data will. ****************** GI / Soft Tissue Sarcoma: Tepper 12/00 AU: Mellgren A, Sirivongs P, Rothenberger DA, Madoff RD, Garcia-Aguilar J. TI: Is local excision adequate therapy for early rectal cancer? SO: Dis Colon Rectum. 2000 Aug;43(8):1064-71; discussion 1071-4. ID: PMID: 10950004 UI: 20404937 Abstract: PURPOSE: Radical surgery of rectal cancer is associated with significant morbidity, and some patients with low-lying lesions must accept a permanent colostomy. Several studies have suggested satisfactory tumor control after local excision of early rectal cancer. The purpose of this study was to compare recurrence and survival rates after treating early rectal cancers with local excision and radical surgery. METHODS: One hundred eight patients with T1 and T2 rectal adenocarcinomas treated by transanal excision were compared with 153 patients with T1N0 and T2N0 rectal adenocarcinomas treated with radical surgery. Neither group received adjuvant chemoradiation. Mean follow-up time was 4.4 years after local excision and 4.8 years after radical surgery. RESULTS: The estimated five-year local recurrence rate was 28 percent (18 percent for T1 tumors and 47 percent for T2 tumors) after local excision and 4 percent (none for T1 tumors and 6 percent for T2 tumors) after radical surgery. Overall recurrence was also higher after local excision (21 percent for T1 tumors and 47 percent for T2 tumors) than after radical surgery (9 percent for T1 tumors and 16 percent for T2 tumors). Twenty-four of 27 patients with recurrence after local excision underwent salvage surgery. The estimated five-year overall survival rate was 69 percent after local excision (72 percent for T1 tumors and 65 percent after T2 tumors) and 82 percent after radical surgery (80 percent for T1 tumors and 81 percent for T2 tumors). Differences in survival rate between local excision and radical surgery were statistically significant in patients with T2 tumors. CONCLUSIONS: Local excision of early rectal cancer carries a high risk of local recurrence. Salvage surgery is possible in most patients with local recurrence, but may be effective only in patients with T1 tumors. When compared with radical surgery, local excision may compromise overall survival in patients with T2 rectal cancers. Editor's comments: There is a great deal of interest in the use of sphincter preservation techniques for rectal cancer, either using low anterior resections (at times with coloanal anastomoses) or local excision techniques. Either of these can be combined with radiation therapy and 5-FU based chemotherapy. Previously, some of the local recurrence data has been discussed in this forum with local excision plus RT from the Intergroup study (Steele et al) showing local recurrence rates higher than expected. This has led some to argue that radiation therapy is not adding much to the outcome. The present abstract comes from an excellent group of colo-rectal surgeons at the Univ of Minn and shows very high local recurrence rates with surgical resection alone for both stage T1 and T2 tumors. In addition, the survival rates of conservatively treated patients were worse than in a group of patients treated with more radical surgery. This strongly implies two things. First, the addition of radiation therapy and chemotherapy to local excision produces a substantial improvement in local control (and perhaps in survival). Secondly, conservative therapy of these patients must be undertaken with great care and both patients and physicians need to understand the limitations inherent in this conservative approach. One cannot directly extrapolate from other tumors and assume that the approach of limited surgery with postoperative radiation therapy can be widely applicable. The challenge in the future remains both to define more accurately the patients who are appropriate for conservative therapy and to devise more effective ways of managing these patients while maintaining sphincter preservation. ****************** GU: Roach 12/00 AU: Kattan MW, Zelefsky MJ, Kupelian PA, Scardino PT, Fuks Z, Leibel SA. TI: Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. SO: J Clin Oncol. 2000 Oct 19;18(19):3352-9. URL: http://www.jco.org/cgi/content/full/18/19/3352 ID: PMID: 11013275 UI: 20469576 Abstract: PURPOSE: Several studies have defined risk groups for predicting the outcome after external-beam radiotherapy of localized prostate cancer. However, most models formed patient risk groups, and none of these models considers radiation dose as a predictor variable. The purpose of this study was to develop a nomogram to improve the accuracy of predicting outcome after three-dimensional conformal radiotherapy. MATERIALS AND METHODS: This study was a retrospective, nonrandomized analysis of patients treated at the Memorial Sloan-Kettering Cancer Center between 1988 and 1998. Clinical parameters of the 1,042 patients included stage, biopsy Gleason score, pretreatment serum prostate-specific antigen (PSA) level, whether neoadjuvant androgen deprivation therapy was administered, and the radiation dose delivered. Biochemical (PSA) treatment failure was scored when three consecutive rises of serum PSA occurred. A nomogram, which predicts the probability of remaining free from biochemical recurrence for 5 years, was validated internally on this data set using a bootstrapping method and externally using a cohort of patients treated at the Cleveland Clinic, Cleveland, OH. RESULTS: When predicting outcomes for patients in the validation data set from the Cleveland Clinic, the nomogram had a Somers' D rank correlation between predicted and observed failure times of 0.52. Predictions from this nomogram were more accurate (P: <.0001) than the best of seven published risk stratification systems, which achieved a Somers' D coefficient of 0. 47. CONCLUSION: The development process illustrated here produced a nomogram that seems to predict more accurately than other available systems and may be useful for treatment selection by both physicians and patients. Editor's comments: The recent article from Kattan et al. caught my attention this month! It brings to mind an old rock song that goes something like this: "you may not get what you want, but you get what you need". Unfortunately in this case, we are getting what they want, namely: "a Predictive Nomogram" for PSA failure but not what we need: "a way to predict survival". Why do I make such an outrageous assertion about this well written paper by these accomplished experts? Reason #1 In our analysis of long term survivors form RTOG trials, we had pretreatment PSAs on > 400 patients. Pretreatment PSA only predicted disease specific survival if it was > 100 and the patients were otherwise low risk and treated with RT alone. PSA > 20 ng/ml predicted distant failure (Roach et al. IJROBP 47: 609-615 and 617-627). Gleason score was the most important predictor of death. Their model weights PSA too highly and does not give very many points based on Gleason score. The importance of GS as an important predictor is supported by data from Fox chase (Lee et al.) as well as surgical series. Reason #2 Dose in their model is given a set of points independent of the risk groups. Hanks' and Pollack's data suggest patients with PSA > 10 benefit, but lower PSA cases don't. Their model ignores such subgroups. Reason #3 RTOG 8610 is positive for survival for Gleason 2-6 patients but not for higher risk patients, again their model ignores subgroups that may have selective benefits of hormonal therapy. Reason #4 Their follow-up is too short. Median FU=~29 mo. For "non-failing patients". If you believe the data from Vicinis paper that discusses the critical importance of FU you can not be confident about who is or is not free of disease with such short FU. ... you get my point. Nice try but "no cigar". Stay tuned with the RTOG and prospective trials and we promise that we will get you "what you need"! ****************** CNS: Bauman 12/00 AU: Rodrigues GB, Waldron JN, Wong CS, Laperriere NJ. TI: A retrospective analysis of 52 cases of spinal cord glioma managed with radiation therapy. SO: Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):837-42. URL: http://hub.elsevier.com/pii/S0360301600006908 ID: PMID: 11020582 UI: 20476656 Abstract: Purpose: To describe the outcome of primary spinal cord glioma treated with radiation therapy after surgery and to identify variables predictive of outcome.Methods and Materials: A chart review of 52 patients with a diagnosis of spinal cord non-ependymoma glioma at the Princess Margaret Hospital was conducted. Thirty-two patients (62%) were male and 20 (38%) were female. Median age was 32 years (2-76 years). Median follow-up was 3.7 years (2 months to 27 years). Initial surgical management consisted of biopsy alone in 27 (52%) cases, subtotal resection in 20 (38%) cases, and gross total resection in 5 (10%) cases. All patients received postoperative radiation therapy; median total dose was 50 Gy, given in 25 daily fractions (20-60 Gy). Actuarial survival rates were calculated and the influence of patient-, tumor-, and treatment-related variables on outcome was determined. Results: Five-year overall, cause-specific, and progression-free survivals were 54%, 62%, and 58%, respectively. Ten-year survivals were 45%, 50%, and 43%, respectively. A total of 29 (56%) patients died during the period of review. For 23 (79%) of these patients, death was cancer specific. Progression of tumor was documented in 28 of 52 (54%) patients. The following factors predicted for improved outcome on univariate analysis: age < 18 years, low-grade histology, and length of symptoms prior to diagnosis > 6 months. Conclusion: The outcome of patients in this series is consistent with that of other similar published reports. Specific recommendations are made for the management of this tumor. Editor's comments: This contemporary retrospective review of patients with primary spinal cord glioma is one of the larger series reported in the literature. No surprises, but a good summary of the literature is presented. An earlier series reported by the authors reported on primary spinal cord ependymomas (IJROBP 1993 27:223-229). A recent issue of the Journal of Neuro-Oncology (vol 47, 2000) has a number of nice reviews on primary spinal cord tumors. ****************** Radiobiology: Withers 12/00 AU: Tome WA, Fowler JF TI: Selective boosting of tumor subvolumes. SO: Int J Radiat Oncol Biol Phys. 2000 Sep 1;48(2):593-9. URL: http://hub.elsevier.com/pii/S0360301600006660 ID: PMID: 10974480 UI: 20432162 Abstract: PURPOSE AND BACKGROUND: It is no longer considered mandatory to deliver a uniform dose to the tumor volume in radiotherapy. Non-uniform doses are unavoidable in brachytherapy and in stereotactic radiosurgery, with often good results. Deliberately non-uniform doses may increase tumor control probability (TCP) and enable steeper dose gradients outside the treated volume to be achieved. New methods of tumor imaging might show regions of specific activity or hypoxia which could be selectively targeted. This paper investigates by modeling the effect of boosting, by dose ratios up to 2, for a range of tumor subvolumes. METHODS AND MATERIALS: A standard linear-quadratic algorithm was used to define the dose-response curve for tumors of various volumes (numbers of clonogenic cells), radiosensitivity (SF(2)), assumed slope (gamma(50)) and dose for 50% tumor control (TCD(50)). Curves of tumor control probability (TCP) were constructed to show the increase of TCP, as a function of the ratio of boost dose to the TCD(50), above the baseline 50% TCP, for a set of different proportions of tumor volume boosted. RESULTS: Calculated values of TCP increased rapidly with both boost dose ratio and with proportion of volume boosted. The increase in TCP reached a plateau after boost dose ratios of 1.2-1.3, as has been noted before, except where very large proportions of tumor volume exceeding 90% were boosted. Quite large increases of TCP, to about 75%, could be achieved if the gamma(50) slope was steep, and especially in small tumors (having fewer cells). Radiosensitivity was not an independent factor because radiosensitive tumors had a low TCD(50) and this was the baseline dose considered as unity. CONCLUSION: There were few situations where a boost dose ratio exceeding 1.3 appeared to be worthwhile or necessary. Significant increases of TCP, up from 50% to 75%, might therefore be achieved for a small increase in risk of necrosis, where a substantial proportion of tumor volume (60-80%) could be boosted. Editor's comments: This paper illustrates in a quantitative manner, the complexities underlying any attempt at predicting the potential advantages (or disadvantages) of increasing the degree of inhomogeneity of dose throughout a tumor. The major determinants are, of course, the proportion of the tumor clonogens exposed to higher or lower doses, the magnitude of the inhomogeneity of dose, and the steepness of the curve for tumor control probability (TCP). Many factors influence the steepness of the TCP curve and one of the conclusions from this modeling is that we need better ways of identifying the factors most likely to limit radiocurability in the individual patient. It is clearly impossible to illustrate all possible combinations of dosimetric and radiobiologic heterogeneity, but the authors provide some quantitative perspective on the importance of the several variables affected by introducing inhomogeneities in dose, as increasingly happens with brachytherapy, stereotactic irradiation and conformal irradiation with or without IMRT. This paper provides useful illustrative figures (most radiation oncologists can skip the algebra) and well-selected references. ****************** Health Services Research: Hayman 12/00 No Reference Selected ****************** Radiation Biophysics: Chen 12/00 AU: Nath R, Amols H, Coffey C, Duggan D, Jani S, Li Z, Schell M, Soares C, Whiting J, Cole PE, Crocker I, Schwartz R. TI: Intravascular brachytherapy physics: report of the AAPM Radiation Therapy Committee Task Group no. 60. American Association of Physicists in Medicine. SO: Med Phys. 1999 Feb;26(2):119-52. ID: PMID: 10076966 UI: 99174584 Abstract: Recent preclinical and clinical studies indicate that irradiation using ionizing radiation in the dose range of 15 to 30 Gy may reduce the occurrence of restenosis in patients who have undergone an angioplasty. Several delivery systems of intravascular brachytherapy have been developed to deliver radiation doses in this range with minimal normal tissue toxicity. In late 1995 the American Association of Physicists in Medicine (AAPM) formed a task group to investigate these issues and to report the current state of the art of intravascular brachytherapy physics. The report of this task group is presented here. Editor's comments: This month's suggested physics reading is outside my area of expertise, but nevertheless is an important area for medical physics. The article was published in early 1999, and represents the collective assessment of a group of experts on the current state of art of the subject. I chose this article for two reasons: 1) there is a growing interest in this field now that devices for this treatment are FDA approved and 2) this article is one of the most often quoted according to the Science Citation Index on this particular topic. ****************** Happy Holidays! Brian J. Goldsmith, M.D. Moderator, IROJC