From owner-radoncjc@net.bio.net Tue Sep 5 21:11:49 2000 To: radoncjc@net.bio.net From: "Brian Goldsmith MD" Subject: September 2000 IROJC, Part I of II Date: Tue, 05 Sep 2000 16:04:58 -0700 Message-Id: <20000905201143.65F1717AFD@mercury.hgmp.mrc.ac.uk> September 2000 Internet Radiation Oncology Journal Club (IROJC) Part I of II ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 64th collection of references suggested for attention and discussion by the IROJC's Board of Editors: Sarah Donaldson, M.D. Editor, Pediatric Radiation Oncology Robert Foote, M.D. Editor, Head and Neck / Skin Radiation Oncology Abram Recht, M.D. Editor, Breast Radiation Oncology Rich Hoppe, M.D. Editor, Reticuloendothelial System Radiation Oncology Dan Petereit, M.D. Editor, Gynecological Radiation Oncology Andrew Turrisi, M.D. Editor, Lung and Mediastinum Radiation Oncology Joel Tepper, M.D. Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology Mack Roach, M.D. Editor, Genitourinary Radiation Oncology Glenn Bauman, M.D. Ph.D. Editor, Central Nervous System Radiation Oncology Rod Withers, M.D., D.Sc. Editor, Radiobiology James Hayman, M.D. Editor, Health Services Research George Chen, Ph.D. Editor, Radiation Biophysics ----------------------------------------------------- You're encouraged to critically review this set of references and respond by posting your comments to the IROJC readership at radoncjc@net.bio.net. ----------------------------------------------------- Peds: Donaldson 9/00 AU: Merchant TE; Nguyen D; Walter AW; Pappo AS; Kun LE; Rao BN. TI: Long-term results with radiation therapy for pediatric desmoid tumors. SO: Int J Radiat Oncol Biol Phys 2000 Jul 15;47(5):1267-71. Abstract: PURPOSE: To retrospectively review the treatment and outcome of pediatric patients with desmoid tumor who received radiation therapy at a single institution. MATERIALS AND METHODS: Thirteen pediatric patients received radiation therapy for desmoid tumor at St. Jude Children's Research Hospital between 1962 and 1998. Only 2 of the patients reviewed received treatment prior to 1976. The median dose of external beam irradiation was 50 Gy. RESULTS: At the time of this report, 10 of 13 patients have had tumors that recurred after radiation therapy and 3 have died from their disease. One additional patient was harboring a recurrence, and 1 had not been followed long enough to suggest that the patient had achieved disease control. One patient remained locally controlled after radiation therapy with long-term follow-up (196 months). The median time to recurrence following radiation therapy was 19 months (range, 3-135 months). Eight of the 13 patients suffered substantial tumor and treatment-related morbidity. CONCLUSIONS: Desmoid tumors in pediatric patients are locally aggressive tumors that are likely to recur after radiation therapy. Alternatives to radiation therapy should be sought for the treatment of these tumors, and efforts should focus on low-morbidity therapies aimed at inhibiting the growth of these unique tumors. Editor's comments: This article reviews a single institutional uniquely pediatric experience and provides summary data which are sobering. Why are these results less satisfactory than that reported in other series of mixed ages? Some possible explanations and concerns arising this article include: 1. This is a small series, only 13 patients. 2. The dose was low in the early years of this experience, with overall doses lower than that generally used in adults. 3. Eight of the 13 children had already recurred before receiving radiotherapy, thus these cases may have been selected because they have particularly aggressive tumors or aggressive biology. 4. No data are provided about the volume irradiated, or the patterns of recurrence. We assume the recurrences were local, meaning in the center of the irradiated field, but marginal recurrences could contribute. Unfortunately the authors recommend "alternative measures should be tested", words easier said than done. There are no good measures alternative to complete surgical resection, and high dose-large volume external beam irradiation. The role of chemotherapy is under study, and not yet clear. Therefore, this paper is a good one to use for reference, but not necessarily to establish treatment policy. I am not convinced that radiotherapy should be avoided in children. If used, however, it needs to be to a high dose, and large volume, ideally to site with negative surgical margins. ****************** Head/Neck/Skin: Foote 9/00 AU: Fu KK; Pajak TF; Trotti A; Jones CU; Spencer SA; Phillips TL; Garden AS; Ridge JA; Cooper JS; Ang KK. TI: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003 SO: Int J Radiat Oncol Biol Phys 2000 Aug 1;48(1):7-16. Abstract: PURPOSE: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. METHODS AND MATERIALS: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1. 2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. RESULTS: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control (p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. CONCLUSIONS: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased. Editor's comments: See also accompanying editorial comments by Withers and Peters pg 1-2, and Fowler and Harari pg 3-6. ****************** GYN: Petereit 9/00 AU: Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, De Winter KA, Lutgens LC, van den Bergh AC, van de Steen-Banasik E, Beerman H, van Lent M. TI: Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. SO: Lancet. 2000 Apr 22;355(9213):1404-11. URL: http://www.thelancet.com/newlancet/sub/issues/vol355no9213/article1404.html Abstract: BACKGROUND: Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma. METHODS: Patients with stage-1 endometrial carcinoma (grade 1 with deep [> or =50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints. FINDINGS: Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0.001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0.31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0.37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0.0001). Two-thirds of the complications were grade 1. Grade 3-4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0.02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors. INTERPRETATION: Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion. Editor's comments: Creutzberg reported the results of a multi-center randomized European trial which investigated the efficacy of adjuvant pelvic radiotherapy for women with stage I endometrial cancer (1). All patients underwent a TAH/BSO with an assessment of the peritoneal cytology without a lymphadenectomy. Patients were eligible for randomization if they met the following criteria: grade 1 with > 50% myometrial invasion (IC); grade 2 with any degree of myometrial invasion (IB or IC); and grade 3 with < 50% myometrial invasion (IB). 715 patients with a minimum follow-up of 5 years were either observed or treated to 46 Gy with no brachytherapy. The 5-year acturial survival was 81% in the RT group and 85% in the control group (P=0.31). Loco-regional recurrences (vagina, pelvis or both) were reduced from 14% to 4% with the addition of pelvic radiotherapy. Multivariate analysis demonstrated a pelvic failure rate of 18% in the control group and 5% in the radiated group for high-risk patients -- age > 60 years with grade 1/2 tumors that were deeply invasive (stage IC) or age > 60 years with grade 3 tumors that were superficially invasive (stage IC). 73% of the local recurrences were observed in the vagina. The 3-year survival for patients with an isolated vaginal recurrence who received salvage radiotherapy was nearly 70%. Patients who received adjuvant radiotherapy experienced a 2% significant complication rate (grade 3/4-primarily enteric) as opposed to 0.3% in those observed. Protocol violations were recorded in 4% of the patients. In the RT group, 15 of 354 patients did not receive treatment; whereas 6 of 361 patients randomized to observation received radiation by request. An additional 7 patients (2%) did not complete the course of radiation because of acute toxicities. The authors recommend observation for patients < 60 years of age and for patients with grade 2, stage IB tumors. Below are some of my concerns/observations regarding the study: 1) Relatively low-risk patients were included: grade 2/stage IB disease, 2) One of the most important groups was excluded: grade 3/stage IB disease, 3) As per recommended guidelines, patients were analyzed on the intent to treat basis; however, 22 patients (6.2%) either did not receive radiation, or did not complete the radiation. Also, 1.7% of the control group did receive treatment. With the relatively low number of events, this may be of significance. 4) Extremely high salvage rates were observed for patients who experienced a vaginal cuff recurrence (70%). This is much higher compared to other published series where salvage rates are about 30-40%. This may be a reflection of close follow-up. The follow-up for patients who recurred is probably not long enough to determine whether or not these patients will ultimately die of their disease. 5) Survival may not be the best clinical endpoint for this patient population. In this series, most deaths were not from endometrial cancer. The majority were from either cardiovascular disease or from a second cancer. 6) These patients did not have surgical staging of the lymph nodes and appeared to do as well when compared to US trials [3]. There is definitely a trend amongst US gynecologic oncologists to completely stage the pelvic and sometimes the low para-aortic lymph nodes because of a "perceived" survival benefit. Our European colleageues, per this manuscript, state that "because its benefit is unclear, lymphadenectomy cannot be considered a standard procedure in stage I endometrial cancer". There is now the third randomized trial investigating the efficacy of pelvic radiotherapy (1-3). How does this trial assist us in managing these patients? As a strong believer in vaginal cuff brachytherapy alone, I believe this trial does support this practice. In addition, there is morbidity in delivering pelvic radiotherapy. For purposes of closure and some resolution of this issue, I included a section from my 2000 ASTRO refresher course that I hope will be of some assistance. Adjuvant Radiotherapy For Endometrial Cancer: Suggested Guidelines by Degree of Myometrial Invasion and Grade: None (Stage IA): G1 None G2 None G3 VCB Inner 1/3 (Stage IB): G1 VCB G2 VCB G3 VCB Middle 1/3 (Stage IB/IC): G1 VCB G2 Pelvic* or VCB G3 Pelvic* Outer 1/3 (Stage IC): G1 Pelvic* G2 Pelvic* G3 Pelvic* G-grade; VCB-vaginal cuff brachytherapy; Pelvic-pelvic radiotherapy *Consider vaginal cuff boost in patients with lower uterine segment involvement. These are guidelines only. Other considerations include the extent of surgical staging, risk factors that would preclude pelvic radiation, presence of LVI (lymphvascular space invasion) and patient desire. For example, the data from Elliot et al. (4) would suggest the recurrence patterns are primarily vaginal cuff in patients with grade 3 tumors that invade the inner one-third of the myometrium, and grade 1 lesions with middle one-third invasion. Vaginal cuff brachytherapy in an acceptable alternative to pelvic radiotherapy, especially if these patients are well-staged. In addition, vaginal cuff brachytherapy might yield a wider therapeutic window in patients with grade 2 or 3 deeply invasive tumors if a complete lymphadenectomy has been performed. The data from Chadha (5) and Anderson (6) would support this treatment strategy. On the other hand, vaginal cuff brachytherapy is probably undertreatment for incompletely staged patients with grade 2 or 3 tumors that invade more than one-third of the myometrium. The clinical trial that desperately needs to be investigated is pelvic radiotherapy versus vaginal cuff brachtherapy in stage I disease-stratifying patients on whether or not they have been thoroughly staged. This protocol has been proposed to the GOG corpus committee numerous times. However, due to strong institutional bias this study will probably never be completed in the US in a cooperative group setting. 1. Creutzberg CL, van Putten WL, Koper PC, et al. Treatment morbidity in patients with endometrial cancer: results from a multicenter randomized trial. Lancet 2000;355:1404-1411. 2. Aalders J, Abeler V, Kolstad P, et al. Postoperative external irradiation and prognostic parameters in Stage I endometrial carcinoma. Obstetrics and Gynecology 1980;56:419-427. 3. Roberts JA, Brunetto VL, Keys HM, et al. A phase III randomized study of surgery vs. surgery plus adjunctive radiation therapy in intermediate-risk endometrial. Gynecologic Oncology 1998;68:135. 4. Elliott P, Green D, Coates A, et al. The efficacy of postoperative vaginal irradiation in preventing vaginal recurrence in endometrial cancer. International Journal of Gynecological Cancer 1994;4:84-93. 5. Chadha M, Nanavati PJ, Liu P, et al. Patterns of failure in endometrial carcioma stage IB grade 3 and IC patients treated with vaginal cuff brachytherapy alone. Gynecologic Oncology 1999;72:448. 6. Anderson JM, Stea B, Hallum AV, et al. High-Dose-Rate Postoperative Vaginal Cuff Irradiation Alone For State IB And IC Endometrial Cancer. International Journal of Radiation Oncology, Biology and Physics 2000;46:417-425. ****************** GI / Soft Tissue Sarcoma: Tepper 9/00 AU: Camma C; Giunta M; Fiorica F; Pagliaro L; Craxi A; Cottone M. TI: Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. SO: JAMA 2000 Aug 23-30;284(8):1008-15. URL: http://jama.ama-assn.org/issues/v284n8/rfull/jma00002.html PDF: http://jama.ama-assn.org/issues/v284n8/rpdf/jma00002.pdf Abstract: CONTEXT: The benefit of adjuvant radiotherapy for resectable rectal cancer has been extensively studied, but data on survival are still equivocal despite a reduction in the rate of local recurrence. OBJECTIVE: To assess the effectiveness of preoperative radiotherapy followed by surgery in the reduction of overall and cancer-related mortality and in the prevention of local recurrence and distant metastases. DATA SOURCES: Computerized bibliographic searches of MEDLINE and CANCERLIT (1970 to December 1999), including non-English sources, were supplemented with hand searches of reference lists. The medical subject headings used were rectal cancer, radiotherapy, surgery, RCT, randomized, and clinical trial. STUDY SELECTION: Studies were included if they were randomized controlled trials (RCTs) comparing preoperative radiotherapy plus surgery with surgery alone and if they included patients with resectable histologically proven rectal adenocarcinoma, without metastatic disease. Fourteen RCTs were analyzed. DATA EXTRACTION: Data on population, intervention, and outcomes were extracted from each RCT according to the intention-to-treat method by 3 independent observers and combined using the DerSimonian and Laird method. DATA SYNTHESIS: Radiotherapy plus surgery compared with surgery alone significantly reduced the 5-year overall mortality rate (odds ratio [OR] 0.84; 95% confidence interval [CI], 0.72-0.98; P =.03), cancer-related mortality rate (OR, 0.71; 95% CI, 0.61-0.82; P<.001), and local recurrence rate (OR, 0.49; 95% CI, 0.38-0.62; P<.001). No reduction was observed in the occurrence of distant metastases (OR, 0.93; 95% CI, 0.73-1.18; P =.54). CONCLUSIONS: In patients with resectable rectal cancer, preoperative radiotherapy significantly improved overall and cancer-specific survival compared with surgery alone. The magnitude of the benefit is relatively small and criteria are needed to identify patients most likely to benefit from adjuvant radiotherapy. JAMA. 2000;284:1008-1015. Editor's comments: The precise role of adjuvant radiation therapy in rectal cancer continues to be controversial. Most studies using radiation therapy alone have not shown survival advantage, with the notable exception being the Swedish trial from 3 years ago. This meta-analysis shows an advantage in survival, cancer related mortality rate and local control with the use of preoperative radiation therapy alone. This is somewhat remarkable since a number of these trials were old, used very low dose radiation therapy, with minimal patient selection and sometimes with very large fields. Nonetheless advantages were seen in all parameters, emphasizing the point that local control does matter. No advantage was seen in the rate of distant metastases. A few factors lead to even more confidence in the data. More of an advantage was seen with higher radiation dose, complications were higher with high dose per fraction and very large fields, less effect was seen in Stage A disease. This level of consistency is quite reassuring that the data is logical. The question which is still unanswered is precisely which patients need to be treated with radiation therapy. It is clear that local recurrence occurs in a relatively small percentage of patients and we need to be able to better define those patients to avoid unnecessary irradiation. In addition, I think adds strength to the argument that preoperative radiation therapy is preferable to postoperative treatment, since postoperative studies have not shown evidence of the same survival advantage. ****************** CNS: Bauman 9/00 AU: Petersen C; Petersen S; Milas L; Lang FF; Tofilon PJ. TI: Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor SO: Clin Cancer Res 2000 Jun;6(6):2513-20. Abstract: The antitumor effects of the selective cyclooxygenase (COX)-2 inhibitor SC-236 alone and in combination with radiation were investigated using the human glioma cell line U251 grown in monolayer culture and as tumor xenografts. On the basis of Western and Northern blot analyses, these cells express COX-2 protein and mRNA to levels similar to those in the human colon carcinoma cell line HT29. Treatment of U251 cells in monolayer culture with 50 microM SC-236 resulted in a time-dependent decrease in cell survival as determined by a clonogenic assay. The cell death induced by SC-236 was associated with apoptosis and the detachment of cells from the monolayer. After 2 days of drug treatment, the cells that remained attached were exposed to graded doses of radiation, and the clonogenic assay was performed. Comparison of the survival curves for drug-treated and untreated cultures revealed that SC-236 enhanced radiation-induced cell death. In these combination studies, SC-236 treatment resulted in a dose-enhancement factor of 1.4 at a surviving fraction of 0.1, with the surviving fraction at 2 Gy (SF2) reduced from 0.61 to 0.31. These data indicate that in vitro SC-236 induces U251 apoptotic cell death and enhances the radiosensitivity of the surviving cells. To extend these investigations to an in vivo situation, U251 glioma cells were grown as tumor xenografts in the hind leg of nude mice, and SC-236 was administered in drinking water. SC-236 alone slowed tumor growth rate, and when administered in combination with local irradiation, SC-236 caused a greater than additive increase in tumor growth delay. These in vitro and in vivo results suggest that the selective inhibition of COX-2 combined with radiation has potential as a cancer treatment. Editor's comments: Petersen et al report a benefit of a COX-2 inhibitor using the U251 malignant glioma cell line. They noted induction of apoptosis by SC-236 when used alone, as well as radiosensitization when combined with radiation with in vitro as well as in vivo studies. COX-2 is an attractive target for many reasons. COX-2 overexpression has been seen in several tumor types, and COX inhibition by NSAIDs has been associated with regression of tumors. Available COX-2 inhibitors are well tolerated from a GI point of view and NSAIDs in general have little appreciable CNS toxicity. Many unknowns exist: While Petersen found U251 constitutively expresses COX-2, how many primary malignant gliomas overexpress this enzyme? What is the CNS penetration of COX-2 inhibition and how does this compare to the doses (50 um) used in this study? Non-specific COX inhibitors like ASA and dexamethasone have not been associated with the dramatic apoptotic response in humans that was noted in this study (1 log kill of apoptosis: equivalent to a major surgical debulking) so why should a specific inhibitor be any different? What is the mechanism of radiosensitization and will this apply to primary malignant gliomas? The unknowns notwithstanding, studies like these point the way to novel approaches for malignant beyond surgery + radiation and conventional nitrosourea-based chemotherapy. The potential benefit and anticipated low toxicity makes the combination of a COX-2 inhibitor with radiation an attractive subject for a phase I/II trial... ****************** Brian J. Goldsmith, M.D. Moderator, IROJC From owner-radoncjc@net.bio.net Tue Sep 5 21:14:55 2000 From: "Brian Goldsmith MD" Date: Tue, 05 Sep 2000 13:16:00 -0700 To: radoncjc@net.bio.net Subject: September 2000 IROJC, Part II of II Message-Id: <20000905201449.52A8D17AB5@mercury.hgmp.mrc.ac.uk> September 2000 Internet Radiation Oncology Journal Club (IROJC) Part II of II ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 64th collection of references suggested for attention and discussion by the IROJC's Board of Editors: Sarah Donaldson, M.D. Editor, Pediatric Radiation Oncology Robert Foote, M.D. Editor, Head and Neck / Skin Radiation Oncology Abram Recht, M.D. Editor, Breast Radiation Oncology Rich Hoppe, M.D. Editor, Reticuloendothelial System Radiation Oncology Dan Petereit, M.D. Editor, Gynecological Radiation Oncology Andrew Turrisi, M.D. Editor, Lung and Mediastinum Radiation Oncology Joel Tepper, M.D. Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology Mack Roach, M.D. Editor, Genitourinary Radiation Oncology Glenn Bauman, M.D. Ph.D. Editor, Central Nervous System Radiation Oncology Rod Withers, M.D., D.Sc. Editor, Radiobiology James Hayman, M.D. Editor, Health Services Research George Chen, Ph.D. Editor, Radiation Biophysics ----------------------------------------------------- You're encouraged to critically review this set of references and respond by posting your comments to the IROJC readership at radoncjc@net.bio.net. ----------------------------------------------------- Breast: Recht 9/00 AU: Turner BC; Gumbs AA; Carbone CJ; Carter D; Glazer PM; Haffty BG. TI: Mutant p53 protein overexpression in women with ipsilateral breast tumor recurrence following lumpectomy and radiation therapy. SO: Cancer 2000 Mar 1;88(5):1091-8. URL: http://canceronline.wiley.com/server-java/Arknoid/cancer/0008-543X/v88n5/v88n5p1091-frameset.html Abstract: BACKGROUND: The p53 tumor suppressor gene encodes a nuclear phosphoprotein that is thought to be important to cell cycle regulation and DNA repair and that also may regulate induction of apoptosis by ionizing radiation. Somatic p53 gene mutations occur in 30-50% of breast carcinomas and are associated with poor prognosis. Mutations in the p53 gene result in prolonged stability of the protein that can be detected by immunohistochemical techniques. In a matched case-control study of breast carcinoma patients with ipsilateral breast tumor recurrence (IBTR) following lumpectomy and radiation therapy, the authors investigated the frequency and prognostic significance of somatic p53 mutations as well as the clinical characteristics of patients with these mutations. METHODS: Between 1973 and 1995, there were 121 breast carcinoma patients with IBTR following lumpectomy and radiation therapy, and the authors identified 47 patients in whom the paraffin embedded tissue blocks from the primary breast tumors were available for further molecular analysis. Forty-seven control breast carcinoma patients from the breast carcinoma data base were individually matched to the index cases who did not have IBTR for age, treatment date, follow-up, histology, margin status, radiation dose, and adjuvant treatment. Immunohistochemistry using a monoclonal antibody to mutant p53 protein was used to determine mutant p53 protein overexpression in breast tumors and appropriately scored. RESULTS: A total of 12 of 47 tumor specimens (26%) from index patients with breast tumor relapses demonstrated mutant p53 protein overexpression, whereas only 4 of 47 specimens from controls (9%) demonstrated high mutant p53 immunoreactivity (P = 0.02). The authors found that 9 of 23 patients (39%) with early breast tumor recurrences (recurrences within 4 years of diagnosis) had overexpression of mutant p53 protein, whereas only 1 of 23 control cases (4%) had high mutant p53 protein immunoreactivity (P = 0.003). In contrast, index cases from patients with late breast tumor relapses (more than 4 years after diagnosis), which are more likely to represent de novo breast tumors, and control cases from the breast carcinoma data base without IBTR had similar levels of mutant p53 protein overexpression (P = not significant). The 10-year distant disease free survival for patients with mutant p53 protein was 48%, compared with 67% for breast carcinoma patients without detection of mutant p53 protein (P = 0. 08). The authors found that 13 of 14 primary breast tumors (93%) with mutant p53 protein overexpression were estrogen receptor negative (P = 0.01) and 11 of 14 (79%) were progesterone receptor negative (P = not significant). CONCLUSIONS: In a matched case-control study, overexpression of mutant p53 protein has prognostic significance with respect to IBTR following lumpectomy and radiation therapy. Breast tumors with p53 mutations are generally estrogen receptor negative and are associated with compromised distant disease free survival. Copyright 2000 American Cancer Society. Editor's comments: There are few data on how p53 status affects the outcome of radiotherapy in patients with breast cancer. This excellent study suggests that p53 protein overexpression may be a risk factor for early local failures after breast-conserving therapy, but not late one (those more than 4 years after treatment). However, cases were not matched with controls for two factors likely to be confounded with p53 status: namely, tumor grade and estrogen receptor-protein status. Since both these factors themselves have been associated with increased risks of local failure in some series, the impact of p53 status cannot be separated from them in this series. Thus, the role of p53 in this setting remains uncertain, especially as other studies do not show it to have an impact. (For an excellent, very recent review of this subject - as well as the impact of HER2 and BCL2 - see Hamilton A and Piccart M, Ann Oncol 2000;11:647-663). ****************** RES: Hoppe 9/00 AU: Groves FD; Linet MS; Travis LB; Devesa SS. TI: Cancer surveillance series: non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995. SO: J Natl Cancer Inst 2000 Aug 2;92(15):1240-51. URL: http://jnci.oupjournals.org/cgi/content/full/92/15/1240 PDF: http://jnci.oupjournals.org/cgi/reprint/92/15/1240 Abstract: BACKGROUND: Clinical investigations have shown prognostic heterogeneity within the non-Hodgkin's lymphomas (NHLs) according to histology, but few descriptive studies have considered NHLs by subgroup. Our purpose is to assess the demographic patterns and any notable increases in population-based rates of different histologic subgroups of NHL. METHODS: Using data collected by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, we calculated incidence rates for the major clinicopathologic categories of NHL by age, race, sex, geographic area, and time period. RESULTS: Among the 60 057 NHL cases diagnosed during the period from 1978 through 1995, total incidence (per 100 000 person-years) was 17.1 and 11.5 among white males and females, respectively, and 12.6 and 7.4 among black males and females, respectively. However, rates for follicular NHLs were two to three times greater among whites than among blacks, with little sex variation. Blacks demonstrated much higher incidence than whites for peripheral T-cell NHL, with the incidence rates higher in males than in females. For other NHL subgroups, the incidence rates for persons less than 60 years of age were generally higher among males than among females, with little racial difference; at older ages, the rates were higher among whites than among blacks, with little sex difference. High-grade NHL was the most rapidly rising subtype, particularly among males. Follicular NHL increased more rapidly in black males than in the other three race/sex groups. Overall, the broad categories of small lymphocytic, follicular, diffuse, high-grade, and peripheral T-cell NHL emerged as distinct entities with specific age, sex, racial, temporal, and geographic variations in rates. CONCLUSIONS: Findings from our large, population-based study reveal differing demographic patterns and incidence trends according to histologic group. Future descriptive and analytic investigations should evaluate NHL risks according to subtype, as defined by histology and new classification criteria. Editor's comments: This report analyzes more than 60,000 cases of nHL included in the SEER program between 1978 and 1995. The tabular data and figures break out the data very nicely by histologic type. Sites of extranodal involvement are presented in detail (most common: skin, stomach, brain, small intestine and lung). The discussion includes an excellent review of risk factors related to functional immunologic impairment, specific infectious agents, blood transfusions, agricultural and pesticide exposures, lifestyle factors, and genetic factors. ****************** Lung/Mediastinum: Turrisi 9/00 AU: Choy H, Devore RF 3rd, Hande KR, Porter LL, Rosenblatt P, Yunus F, Schlabach L, Smith C, Shyr Y, Johnson DH. TI: A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study). SO: Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):931-7. Abstract: PURPOSE: We conducted a prospective phase II study to determine the response rate, toxicity, and survival rate of concurrent weekly paclitaxel, carboplatin, and hyperfractionated radiation therapy (paclitaxel/carboplatin/HFX RT) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer (NSCLC). The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. METHODS AND MATERIALS: Forty-three patients with unresectable stage IIIA and IIIB NSCLC from the Vanderbilt Cancer Center and Affiliate Network (VCCAN) institutions were entered onto the study from June 1996 until May 1997. Weekly intravenous (IV) paclitaxel (50 mg/m(2)/l-hour) and weekly carboplatin (AUC 2) plus concurrent hyperfractionated chest RT (1.2 Gy/BID/69.6 Gy) were delivered for 6 weeks followed by 2 cycles of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). RESULTS: Forty-two patients were evaluable for response and toxicities. Three patients achieved a complete response (7.2%) and 30 patients achieved a partial response (71.4%), for an overall response rate of 78.6% [95% C.I. (66.2%-91.0%)]. The 1- and 2-year overall and progression-free survival rates of all 43 patients were 61.6% and 35% respectively, with a median survival time of 14.3 months. The median follow-up time was 14 months. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (26%). There was an incidence of 7% grade 3 and 9.5% grade 4 pulmonary toxicities. CONCLUSIONS: Weekly paclitaxel, carboplatin, plus concurrent hyperfractionated RT is a well-tolerated outpatient regimen. The response rate from this regimen is encouraging and appears to be at least equivalent to the more toxic chemoradiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/carboplatin/HFX RT in a phase III study. and AU: Socinski MA; Rosenman JG; Schell MJ; Halle J; Russo S; Rivera MP; Clark J; Limentani S; Fraser R; Mitchell W; Detterbeck FC. TI: Induction carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal thoracic radiation therapy in unresectable stage IIIA/B nonsmall cell lung carcinoma: a modified Phase I trial. SO: Cancer 2000 Aug 1;89(3):534-42. URL: http://canceronline.wiley.com/server-java/Arknoid/cancer/0008-543X/v89n3/v89n3p534-frameset.html Abstract: BACKGROUND: A modified Phase I trial was conducted evaluating the incorporation of 3-dimensional conformal radiation therapy (3DCRT) into a strategy of sequential and concurrent carboplatin/paclitaxel in Stage III, unresectable nonsmall cell lung carcinoma (NSCLC). In addition, dose escalation of thoracic conformal radiation therapy (TCRT) from 60 to 74 gray (Gy) was performed. Endpoints included response rate, toxicity, and survival. METHODS: Twenty-nine patients with unresectable Stage III NSCLC were included. Patients received 2 cycles of induction carboplatin (AUC 6) and paclitaxel (225 mg/m(2)/3 hours) every 21 days. On Day 43, concurrent TCRT and weekly (x6) carboplatin (AUC 2) and paclitaxel (45 mg/m(2)/3 hours) was initiated. The TCRT dose was escalated from 60 to 74 Gy in 4 cohorts. RESULTS: The response rate to induction carboplatin/paclitaxel was 52%. Three patients (10%) experienced disease progression during the induction phase. No dose-limiting toxicity was seen during the escalation of the TCRT dose from 60 to 74 Gy. The major toxicity was esophagitis, with 18% of patients developing Radiation Therapy Oncology Group Grade 3 esophagitis. The overall response rate was 70% (1 complete response and 18 partial responses). Survival rates at 1 and 2 years were 69% and 45%, with a median survival of 21 months. The 1-year progression free survival probability was 41% (95% confidence interval, 23-59%). CONCLUSIONS: Incorporation of 3DCRT with sequential and concurrent carboplatin/paclitaxel is feasible, and dose escalation of TCRT to 74 Gy is possible with acceptable toxicity. Overall response and survival rates are encouraging. Accrual is continuing in a Phase II fashion at 74 Gy with sequential and concurrent carboplatin/paclitaxel. Copyright 2000 American Cancer Society. Editor's comments: I apologize for the lack of selections for the past few months and thought a pair of related articles might make up for my dereliction of duty. Both of these offer methods of blending the US favorite chemotherapy in non-small cell lung cancer with new ways of giving radiotherapy. I offer these articles for your consideration because of their similarities and differences and what facts these underscore. The important fact is that we do not have a standard treatment for IIIa/b lung cancer. Those that still like to say that chemotherapy followed by surgery is best can see that these trials produce similar outcomes without surgery. Of course my bone of contention is that if the patients on these trials were entered on the now 7 year old intergroup trial of chemo rads with platinum etoposide either to full dose (61 Gy) or followed by surgery after 45 Gy, that study would be within a few months of completion. It has 385 eligible patients entered. Also, chemotherapy followed by surgery, as lionized by Roth and Rossel, was dealt a blow by the DePierre trial from ASCO 1999. It showed small differences in Stage 1 and 2, but no convincing survival difference in Stage 3 (This study used a Mitomycin and Platinum regimen) The Choy trial used chemotherapy and cycle one concurrent twice daily 1.2 Gy fractions. They treated elective nodes to a dose 43.2 Gy before boosting nodes >2.5 cm and the primary. The pattern of failure doesn't isolate nodal failure, but the most common single relapse site was the brain, and a local component of failure in 45% of the patients that failed. The Socinski trial delayed the concurrent chemoradiotherapy until after two cycles of carbo/taxol. This trial had 29 patients all but one without symptoms from their cancer. The dose was escalated from 60 to 74 Gy with two intervening steps. There were three transient strictures and no local failure reported in this phase I/II study -- but despite excellent survival, more local failure is rumored after expansion to 60 patients the last 31 all at 74 Gy. There were a few induction deaths or progressions before local therapy. Both trials are promising leads. We need to remember that thesecases were selected. We will hear more about such small series, but the poor results will not be published, only the good ones will see print. Are the good results from selection? Fractionation? Timing? Fancy treatment planning and rigorous attention to detail? Total Dose? Paclitaxel/carboplatinum? Salvage chemotherapy? Unfortunately, these questions cannot be posed with small pilots. Also, we can't answer any questions if patients are treated with the hot new drugs and everything else in the bag of tricks. We also cannot apply these optimistic results to the patient that comes in with symptoms from the UNC trial, and only about half had them with the Vanderbilt trial. Local failure is said to be still a problem at these high doses, but will the real maximum dose be compromised if we insist on treating occult disease in nodal bearing regions while we fail to control what we see? And since the brain fails more commonly than any nodal station, why isn't this on the agenda? Pilots are supposed to lead. Unfortunately, I don't know where we are at this stage. Are we lost? ****************** GU: Roach 9/00 AU: Valicenti R; Lu J; Pilepich M; Asbell S; Grignon D. TI: Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials. SO: J Clin Oncol 2000 Jul;18(14):2740-6. URL: http://www.jco.org/cgi/content/full/18/14/2740 Abstract: PURPOSE: We evaluated the effect of external-beam radiation therapy on disease-specific survival (death from causes related to prostate cancer) and overall survival in men with clinically localized prostate cancer. METHODS: From 1975 to 1992, 1,465 men with clinically localized prostate cancer received radiation therapy on four Radiation Therapy Oncology Group phase III randomized trials and were pooled for this analysis. No one received androgen-deprivation therapy with his initial treatment. All original histology had central pathologic review for grading using the Gleason classification system. Total delivered radiation dose ranged from 60 to 78 Gy (median, 68.4 Gy). The median follow-up time was 8 years. RESULTS: A Cox regression model revealed that Gleason score was an independent predictor of disease-specific survival and overall survival. The 10-year disease-specific survival rates by Gleason score were as follows: score of 2 through 5, 85%; score of 6, 79%; score of 7, 62%; and score of 8 through 10, 43%. Stratifying outcome by this important prognostic factor revealed that higher radiation dose was a significant predictor for improved disease-specific survival and overall survival only for those patients whose cancers had Gleason scores of 8 through 10 (P <.05). After adjusting for clinical T stage, nodal status, and age, treating with a higher radiation dose was associated with a 29% lower relative risk of death from prostate cancer and 27% reduced mortality rate (P <.05). CONCLUSION: These data demonstrate that higher-dose radiation therapy can significantly reduce the risk of dying from prostate cancer in men with clinically localized disease. This survival benefit is restricted to men with poorly differentiated cancers. Editor's comments: The Report by Valicenti et al. from the RTOG represents an important contribution worthy of note. This retrospective analysis suggest that patients with high grade prostate cancer actually have a long term survival advantage if they receive higher doses of radiation. This analysis is consistent with the recent report by Fiveash et al. (recently discussed here) demonstrating a steep dose response for high grade tumors. Taken together these reports support the notion that high dose radiotherapy should be considered to be the treatment of choice for patients with high grade prostate cancer. As with prostatectomy it may be impossible to prove that treatment of patients with low grade prostate cancer benefit from treatment, because competing causes of death dominate. With high grade tumors treatment effects appear to be easier to be identified. ****************** Radiobiology: Withers 9/00 No Reference Selected ****************** Health Services Research: Hayman 9/00 AU: Osoba D TI: What has been learned from measuring health-related quality of life in clinical oncology SO: Eur J Cancer 1999 Oct;35(11):1565-70. Abstract: The measurement of health-related quality of life (HRQL) in oncology clinical trials has come of age. Most cooperative clinical trials groups as well as individual institutions have either been measuring, or are starting to measure, HRQL. Over the past decade, much has been learned about how to incorporate HRQL components into multicentre, randomised controlled (phase III) trials and how to collect the data with reasonably low levels of missing information. A selective review, focused primarily on phase III studies, shows that HRQL data are useful for deciding which treatment is preferable when survival rates are similar and for determining whether changes in HRQL, as compared with baseline levels, are related to a treatment or intervention. HRQL information is improving our knowledge of the effects of diseases and their treatments on the patient's ability to function and sense of well-being, and HRQL status is proving to be a more accurate predictor of survival than is performance status. Much more remains to be done, but it is apparent that the inclusion of HRQL in clinical trials has been informative and useful. The increasing frequency of HRQL assessment in clinical trials is evidence of the emergence of a patient-centred philosophy in clinical medicine which, in time, will modify the disease-oriented paradigm under which medical professionals have functioned for the past century. Editor's comments: It is pretty difficult to summarize many of the major issues related to measuring quality of life in oncology in 5 pages but Dr. Osoba has done an admirable in this short review article. Rather than focusing a lot of attention on the instruments themselves, he starts off by discussing some of the issues related to measuring quality of life within phase III clinical trials. Since many of us will not be measuring patients' quality of life ourselves but will need to interpret the results of phase III trials that include quality of life as an endpoint, the emphasis seems well placed. After using several trials to illustrate how important a role quality of life assessments can play in certain types of phase III trials, he then turns his attention to the question of what is a clinically meaningful change in a quality of life score. Finally, he closes with a brief discussion of what issues in quality of life research require further investigation (e.g., dealing with missing data, integrating quality of life results with utility measures, etc). As I find less and less time to keep up with my reading, I have increasingly begun to value the ability of an author to be concise. If you only have 15 minutes to devote to reading an article about outcomes research in the next month I would recommend spending it reading this article. ****************** Radiation Biophysics: Chen 9/00 http://www.nlm.nih.gov/research/visible/visible_human.html points to an announcement for the Third Visible Human Project Conference. In the left frame is a hotlink to APPLICATIONS. Follow this with a later editiion of Internet Explorer (I used 5.5), and you find several applications for viewing Visible Human Data. Using a high performance PC and a fast connection, one can interactively browse through the dataset with any number of data explorer tools. Try the NPAC Visible Human Viewer, developed at Syracuse University to extract images. I used the NPAC/OLDA Visible Human Viewer and was able to view male / female, CT MR or Photo images at high resolution. Loading the image provided an enlarged image. I also tried the Cross Sectional Anatomy viewer from Loyola. The interesting aspect of these sites is a) the tools developed to explore such 3D data sets, including 3D renderings, movies and flybys and b) the speculation that such graphics would become more available for RT planning. ****************** Brian J. Goldsmith, M.D. Moderator, IROJC