From owner-radoncjc@net.bio.net Mon Oct 2 22:57:08 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id D700417A99; Mon, 2 Oct 2000 22:57:04 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 60001) id 6835117A9A; Mon, 2 Oct 2000 22:57:03 +0100 (BST) To: radoncjc@net.bio.net From: Brian@hgmp.mrc.ac.uk, Goldsmith@hgmp.mrc.ac.uk, MD@hgmp.mrc.ac.uk Reply-To: radoncjc@net.bio.net Date: 10/2/00 2:50PM Subject: October 2000 Internet Radiation Oncology Journal Club = Message-Id: <20001002215703.6835117A9A@mercury.hgmp.mrc.ac.uk> Sender: owner-radoncjc@net.bio.net Precedence: bulk October 2000 Internet Radiation Oncology Journal Club (IROJC)=20 -------------------------------------------------------=20 Posting of references for review and discussion=20 -------------------------------------------------------=20 The 65th collection of references suggested for attention and=20 discussion by the IROJC's Board of Editors:=20 Sarah Donaldson, M.D.=20 Editor, Pediatric Radiation Oncology=20 Robert Foote, M.D.=20 Editor, Head and Neck / Skin Radiation Oncology=20 Abram Recht, M.D.=20 Editor, Breast Radiation Oncology=20 Rich Hoppe, M.D.=20 Editor, Reticuloendothelial System Radiation Oncology=20 Dan Petereit, M.D.=20 Editor, Gynecological Radiation Oncology=20 Andrew Turrisi, M.D.=20 Editor, Lung and Mediastinum Radiation Oncology=20 Joel Tepper, M.D.=20 Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology=20 Mack Roach, M.D.=20 Editor, Genitourinary Radiation Oncology=20 Glenn Bauman, M.D. Ph.D.=20 Editor, Central Nervous System Radiation Oncology=20 Rod Withers, M.D., D.Sc.=20 Editor, Radiobiology=20 James Hayman, M.D.=20 Editor, Health Services Research=20 George Chen, Ph.D.=20 Editor, Radiation Biophysics=20 -----------------------------------------------------=20 You're encouraged to critically review this set of references and=20 respond by posting your comments to the IROJC readership at=20 radoncjc@net.bio.net.=20 ----------------------------------------------------- Peds: Donaldson 10/00=20 AU: Breneman JC; Wiener ES. TI: Issues in the local control of rhabdomyosarcoma. SO: Med Pediatr Oncol 2000 Aug;35(2):104-9. Abstract:=20 BACKGROUND: Rhabdomyosarcoma (RMS) is a heterogeneous disease consisting = of several different histologies arising from a variety of anatomic sites. = Approximately half of the children who die of this tumor have failure at = the primary site of involvement, making local control an important = component of therapy. PROCEDURE: Published literature and newly analyzed = data from the Intergroup Rhabdomyosarcoma Study Group (IRSG) regarding = local control of RMS were reviewed. Information regarding the role of = various local control modalities for different primary disease sites is = presented along with new directions for clinical research. RESULTS: Local = control rates for RMS average 80% for group III tumors, with large = variations seen for different anatomic sites. Important gains in functional= outcome for certain sites such as gynecologic system and bladder/prostate = have been achieved by optimizing the use of the various treatment = modalities. Local control at other sites such as the chest and extremities = remains a problem. CONCLUSIONS: Advances in surgical and radiotherapy = techniques coupled with multiagent chemotherapy are providing improved = local control with decreasing morbidity. Optimal outcome is dependent on = close collaboration between surgical, radiotherapy, and pediatric oncology = specialists. Copyright 2000 Wiley-Liss, Inc. Editor's comments:=20 The issues surrounding local control in Rhabdomyosarcoma are complex, and = a function of site, age of the child, organ function/quality of life, and = many many more. The Intergroup Rhabdomyosarcoma Study Group (IRSG) = investigators are working to investigate these factors, clarify previous = misunderstandings, and provide clinicians guidelines to consider when = determining management/treatment approaches for individual patients. This = article reviews many of the important aspects and is excellent reading for = the Radiation Oncologist in practice who is trying to keep up with state = of the art information, as well as the young resident/clinician who is = trying to learn first hand a complex subject. Read and save this paper as = excellent reference material. ******************=20 Head/Neck/Skin: Foote 10/00=20 AU: Davidson J; Gilbert R; Irish J; Witterick I; Brown D; Birt D; Freeman = J; Gullane P. TI: The role of panendoscopy in the management of mucosal head and neck = malignancy-A prospective evaluation. SO: Head Neck 2000 Aug;22(5):449-54. Abstract:=20 BACKGROUND: It is common practice for a panendoscopy to be included in the = evaluation of patients with mucosal head and neck malignancies. Whether = this intervention is efficient or cost-effective has not been established = in our patient population. METHODS: Two hundred twenty-four patients with = squamous cell carcinoma involving the oral cavity, pharynx, larynx, or = neck were evaluated prospectively with panendoscopy and chest x-ray with = or without barium swallow. One hundred fifty-four patients had newly = diagnosed tumors and 70 were previously diagnosed and currently undergoing = symptom-directed investigations. RESULTS: The incidence of synchronous = primary tumors was 2.6% (4 of 154); pulmonary, 1.3%; head and neck mucosa, = 1.3%; and esophageal, 0%. There was no associated morbidity. CONCLUSIONS: = Although there was no associated morbidity, our head and neck oncology = group is of the opinion that routine panendoscopy is not warranted. = Specific indications for this investigation are discussed. Copyright 2000 = John Wiley & Sons, Inc. Head Neck 22: 449-455, 2000. =20 ******************=20 GYN: Petereit 10/00=20 AU: Grogan M; Thomas GM; Melamed I; Wong FL; Pearcey RG; Joseph PK; = Portelance L; Crook J; Jones KD. TI: The importance of hemoglobin levels during radiotherapy for carcinoma = of the cervix. SO: Cancer 1999 Oct 15;86(8):1528-36. URL: http://canceronline.wiley.com/cgi-bin/abstracts/v86n8/v86n8p1528.abstr= act.html PDF: http://canceronline.wiley.com/server-java/Arknoid/cancer/0008-543X/v86= n8/v86n8p1528-frameset.html Abstract:=20 BACKGROUND: It is unclear whether blood transfusion can overcome the = negative impact of anemia before or during radiotherapy (RT) in patients = with carcinoma of the cervix. The objective of this retrospective study = was to examine the impact of anemia and blood transfusion on 605 patients = with carcinoma of the cervix treated with radical RT at 7 centers across = Canada in 1989, 1990, and 1992. METHODS: The data collected included = hemoglobin (Hgb) levels from the time of diagnosis to the end of therapy; = blood transfusions administered; and identifiable patient-, tumor-, and = treatment-related factors. Survival, disease free survival, and pelvic = control analyses were evaluated by univariate and multivariate analysis. = RESULTS: The median follow-up was 41 months (range, 0-92 months). = Presenting Hgb level, average weekly nadir Hgb (AWNH) during RT, and blood = transfusion were correlated significantly with local control, disease free = survival, and overall survival on univariate analysis. However, the AWNH = remained significant on multivariate analysis, whereas Hgb at presentation = and blood transfusion did not. The 5-year survival was 74% for patients = with an AWNH >/=3D 120 g/L, 52% for patients with AWNH levels 110-119 g/L = inclusive, and 45% for patients with AWNH levels < 110 g/L (P < 0.0001). = At each Hgb level, patients who were transfused and maintained a specific = Hgb level had a survival rate that was not significantly different from = patients who were at that level spontaneously. There was a significant = reduction in both pelvic and distant recurrence (P < 0.0001 and P < = 0.0006, respectively) in patients whose AWNH level during RT was >/=3D 120 = g/L compared with < 120 g/L. A reduction in the rate of distant recurrence = was observed in patients with and without pelvic recurrence. CONCLUSIONS: = AWNH is highly predictive of outcome for patients treated with RT for = carcinoma of the cervix. Blood transfusion appears to overcome the = negative prognostic effects of low presenting Hgb levels and AWNH levels. = Copyright 1999 American Cancer Society. Editor's comments:=20 A retrospective study from seven Canadian cancer centers investigated the = importance of anemia and impact of blood transfusions in cervical patients = who underwent radical radiotherapy. Hemoglobin data was collected in = approximately 600 patients: presenting Hgb level, average weekly nadir = Hgb (AWNH) and post-transfusion Hgb levels-all endpoints were correlated = to pelvic control and survival. The following intriguing results were = found: 1) 12% decrease in survival for patients with a Hgb level < 12.0 g/l vs > = 12.0 g/l 2) AWNH levels correlated to survival and pelvic control on = multivariate analysis-second only to tumor stage 3) a stepwise increase = in survival for each AWNH achieved up to 12.0 g/l for transfused and = non-transfused patients. At each Hgb level, transfused patients had the = same outcome as patients who spontaneously achieved the same Hgb level. = 4) The positive impact of transfusions was further studied by subdividing = patients into four groups: high vs low Hgb levels (< vs > 12.0 g/l) and = the impact of transfusions. Patients who presented with a low Hgb level = and were raised to a high level during radiation had outcomes comparable = to those patients who presented and maintained a high Hgb level. 5) The = worst outcome was observed for those patients who presented with a high = Hgb level which subsequently fell during radiotherapy. 6) For patients = with a high Hgb level, both the pelvic and distant failure rates were = lower. Grogan and Thomas present an excellent discussion of their results, = including implications for current practice and future trials. They = suggest keeping the Hgb level above 12.0 g/l during radiotherapy. Their = data strongly suggests that transfusing these patients to a level above = 12.0 g/l and maintaining that level, will potentially overcome the = negative effects of anemia. ******************=20 GI / Soft Tissue Sarcoma: Tepper 10/00=20 No Reference Selected=20 ******************=20 CNS: Bauman 10/00=20 AU: Abrey LE; Yahalom J; DeAngelis LM. TI: Treatment for primary CNS lymphoma: the next step. SO: J Clin Oncol 2000 Sep;18(17):3144-50 URL: http://www.jco.org/cgi/content/abstract/18/17/3144 PDF: http://www.jco.org/cgi/reprint/18/17/3144 Abstract:=20 PURPOSE: The use of preradiotherapy (RT) methotrexate (MTX) has improved = disease control and survival in patients with primary CNS lymphoma = (PCNSL). The reported protocol was designed to optimize and enhance the = chemotherapeutic component of treatment. PATIENTS AND METHODS: Fifty-two = patients were treated with five cycles of high-dose MTX 3.5 g/m(2), = procarbazine 100 mg/m(2)/d, and vincristine 1.4 mg/m(2). Thirty patients = received whole-brain RT (45 Gy). Twenty-two older patients deferred RT to = diminish the risk of delayed neurotoxicity; these patients are compared = with 12 older patients who completed the entire treatment regimen. Most = patients (n =3D 35) received high-dose cytarabine after RT. RESULTS: = Objective response rate to the induction chemotherapy regimen was 90%; = overall median survival is 60 months. Grade 3 or 4 myelosuppression was = seen in 30 patients, primarily in association with cytarabine; grade 3 = nephrotoxicity due to MTX was seen in two patients. Older patients had = similar median survival with or without the addition of RT: 32 versus 33 = months, respectively. However, late neurotoxicity was significantly more = common in those older patients who received RT (P: =3D.00004). Patients = younger than 60 years who received the complete treatment regimen have not = reached median disease-free or overall survival. CONCLUSION: Increasing = the dose of MTX and adding procarbazine and vincristine improved disease = control and overall survival in patients with newly diagnosed PCNSL. = Younger patients in particular fared extremely well with this treatment = regimen. In older patients, deferring whole-brain RT did not compromise = overall survival but did reduce treatment-related toxicity. Editor's comments:=20 Non-randomized studies of chemotherapy combinations similar to that of the = DeAngelis regimen added to cranial radiation suggest significantly = improved survival compared to cranial radiation alone. A recent case = control study reported at ASCO (Schultz, C., Scott, C., DeAngelis, L., = Nelson, D., Nelson, J., Schold, S.and Curran, W.: Radiation Therapy (RT) = Alone Vs. Pre-RT Chemotherapy (CTX) for the Treatment of Primary CNS = Lymphoma(PCNSL): Aged Matched Survival Analysis of RTOG 83-15 and RTOG = 93-10. Proc of Am Soc Clin Oncol (ASCO), New Orleans, LA, J Clin Oncol, 19 = 159a, 2000) confirms the apparent benefit of (neo)adjuvant chemotherapy. = The toxicity of combined chemo-radiation can be considerable in older = (>60) patients as noted by DeAngelis. DeAngelis' work suggests that = chemotherapy alone may be of equivalent palliative benefit in this group = with less toxicity. Caution needs to be exercised in this conclusion as = the groups were not randomized and formal neuropsychologic testing was not = performed. Also, all the younger patients received combined modality. CNS = lymphoma trials in development through the RTOG propose to compare = deferred vs immediate radiation in patients with a CR to induction = chemotherapy. Randomized trials such as these are necessary to confirm = the safety and efficacy of "de-escalation" of therapy by ommission of the = cranial radiation. Also, what about the older patient who does not/will = not tolerate chemotherapy or has a poor radiographic response to chemothera= py? Cranial radiation may still be necessary in this group, despite the = potential toxicity.... ******************=20 Breast: Recht 10/00=20 TI: Favourable and unfavourable effects on long-term survival of radiothera= py for early breast cancer: an overview of the randomised trials. Early = Breast Cancer Trialists' Collaborative Group. SO: Lancet 2000 May 20;355(9217):1757-70. URL: http://www.thelancet.com/newlancet/sub/issues/vol355no9217/article1757= .html Abstract:=20 BACKGROUND: The long-term effects of radiotherapy on mortality from breast = cancer and other causes remain uncertain. METHODS: A meta-analysis was = done of 10-year and 20-year results from 40 unconfounded randomised trials = of radiotherapy for early breast cancer. It involved central review of = individual patients' data on recurrence and cause-specific mortality from = 20000 women, half with "node-positive" disease. Radiotherapy fields = generally included not only chest wall (or breast) but also axillary, = supraclavicular, and internal mammary nodes. FINDINGS: A reduction of = approximately two-thirds in local recurrence was seen in all trials, = largely independent of the type of patient or type of radiotherapy (8.8% = vs 27.2% local recurrence by year 10). Hence, to assess effects on breast = cancer mortality of substantially better local control, results from all = trials were combined. Breast cancer mortality was reduced (2p=3D0.0001) = but other, particularly vascular, mortality was increased (2p=3D0.0003), = and overall 20-year survival was 37.1% with radiotherapy versus 35.9% = control (2p=3D0.06). There was little effect on early deaths, but logrank = analyses of later deaths indicate that, on average after year 2, radiothera= py reduced annual mortality rates from breast cancer by 13.2% (SE 2.5) but = increased those from other causes by 21.2% (SE 5.4). Nodal status, age, = and decade of follow-up strongly affected the ratio of breast cancer = mortality to other mortality, and hence affected the ratio of absolute = benefit to absolute hazard from these proportional changes in mortality. = INTERPRETATION: Radiotherapy regimens able to produce the two-thirds = reduction in local recurrence seen in these trials, but without long-term = hazard, would be expected to produce an absolute increase in 20-year = survival of about 2-4% (except for women at particularly low risk of local = recurrence). The average hazard seen in these trials would, however, = reduce this 20-year survival benefit in young women and reverse it in = older women. AND AU: Van de Steene J; Soete G; Storme G. TI: Adjuvant radiotherapy for breast cancer significantly improves overall = survival: the missing link. SO: Radiother Oncol 2000 Jun;55(3):263-72. Abstract: Background and purpose: The influence of surgical adjuvant radiotherapy on = overall survival of patients with operable breast cancer is still a = controversial subject. The negative result of the EBCTCG meta-analysis = (Early breast cancer trialists', collaborative group. Effects of radiothera= py and surgery in early breast cancer. An overview of the randomised = trials. N. Engl. J. Med. 1995;333:1444-1455) of clinical randomized trials = on adjuvant radiotherapy in breast cancer is in strong contrast with the = Danish 82B, 82C and British Columbia trials (Overgaard M, Hanse PS, = Overgaar J, et al. Postoperative radiotherapy in high-risk premenopausal = women with breast cancer who receive adjuvant chemotherapy. Danish Breast = Cancer Cooperative Group 82b Trial. N. Engl. J. Med. 1997;337:949-955; = Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in = high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: = Danish Breast Cancer Cooperative Group DBCG 82c randomized trial. Lancet = 1999;353:1641-1648; Ragaz J, Jackson S, Le N, et al. Adjuvant radiotherapy = and chemotherapy in node-positive premenopausal women with breast cancer. = N. Engl. J. Med. 1997;337:956-962) showing an impressive survival benefit. = This paper tries to fill in the gap between the conflicting results. = Materials and methods: The 36 trials of the EBCTCG (Early breast cancer = trialists', collaborative group, 1995) were prospectively screened for a = number of objective parameters that are usually not analyzed in review = papers. The odds of death data (and its variance) were borrowed from the = original meta-analysis (Early breast cancer trialists', collaborative = group, 1995) to check whether the objective features were significant = predictors for overall survival benefit.Results: A significant survival = benefit for the radiotherapy arm was found for recent trials (2P<0.05), = large trials (2P<0.03), trials that used standard fractionation (2P<0.02), = and trials with a favourable crude survival (2P<0.03). For these four = parameters clear parameter-effect relations were found. In recent and = large trials the odds reduction was 12.4% (2P=3D0.004).Conclusions: = Surgical adjuvant radiotherapy significantly improves overall survival of = breast cancer patients provided that current techniques are used and = treatment is given with standard fractionation. For the best subgroups we = observed an odds of death reduction of more than 20%. The results of this = study stress the importance of reducing cardiovascular and other late = toxicity in adjuvant radiotherapy for breast cancer. AND AU: Whelan TJ; Julian J; Wright J; Jadad AR; Levine ML. TI: Does locoregional radiation therapy improve survival in breast cancer? = A meta-analysis. SO: J Clin Oncol 2000 Mar;18(6):1220-9. URL: http://www.jco.org/cgi/content/abstract/18/6/1220 PDF: http://www.jco.org/cgi/reprint/18/6/1220 Abstract: PURPOSE: Recent randomized trials in women with node-positive breast = cancer who received systemic treatment report that locoregional radiation = therapy improves survival. Previous trials failed to detect a difference = in survival that results from its use. A systematic review of randomized = trials that examine the effectiveness of locoregional radiation therapy in = patients treated by definitive surgery and adjuvant systemic therapy was = conducted. METHODS: Randomized trials published between 1967 and 1999 were = identified through MEDLINE database, CancerLit database, and reference = lists of relevant articles. Relevant data was abstracted. The results of = randomized trials were pooled using meta-analyses to estimate the effect = of treatment on any recurrence, locoregional recurrence, and mortality. = RESULTS: Eighteen trials that involved a total of 6,367 patients were = identified. Most trials included both pre- and postmenopausal women with = node-positive breast cancer treated with modified radical mastectomy. The = type of systemic therapy received, sites irradiated, techniques used, and = doses of radiation delivered varied between trials. Data on toxicity were = infrequently reported. Radiation was shown to reduce the risk of any = recurrence (odds ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.83), = local recurrence (odds ratio, 0.25; 95% CI, 0.19 to 0.34), and mortality = (odds ratio, 0.83; 95% CI, 0.74 to 0.94). CONCLUSION: Locoregional = radiation after surgery in patients treated with systemic therapy reduced = mortality. Several questions remain on how these results should be = translated into current-day clinical practice. Editor's comments:=20 The role of radiotherapy in reducing mortality from breast cancer and = increasing overall survival rates has been debated for decades. Numerous = randomized trials have shown that radiotherapy substantially reduces the = risk of local-regional failure, but trial results with regards to these = two other endpoints have been mixed. There have been few meta-analyses = performed of these trials. The best-known and most influential have been = those of the The Early Breast Cancer Trialists' Collaborative Group. The = most recent of these did not show an advantage in overall survival at 20 = years for patients receiving radiotherapy following surgery, compared to = those who did not. While there was a statistically-significant reduction = in the risk of breast-cancer related deaths, this was counterbalanced by = an increase in the risk of non-breast cancer mortality (mainly cardiovascul= ar, although the cause of death was not known for many patients), = particularly in women over age 50. However, this analysis included trials = in which breast-conserving surgery, simple mastectomy, or radical = mastectomy, as well as modified radical mastectomy, were used. Patients = with both positive and negative axillary nodes were included. Many of the = trials employed outdated radiotherapy techniques, such as the use of = orthovoltage equipment. Most importantly, this study did not segregate = trials in which systemic therapy was routinely given to patients from = those in which systemic therapy was not used. Finally, many of the older = trials in particular used fraction sizes in excess of 2 Gy, which likely = amplified the risk of cardiac complications substantially, especially when = combined with older treatment techniques. Unfortunately, the subgroup = analyses performed did not segregate these important factors. Thus, the = value of this overview for settling this debate is limited. The meta-analysis from van de Steene and colleagues attempts to rectify = some of these problems by performing the critical subgroup analyses using = information from the 1995 Oxford overview (N Engl J Med 1995;353:1641-8). = However, this effort did not segregate the trials according to the type of = surgery (e.g., mastectomy with axillary dissection versus breast-conserving= therapy). Although their conclusions are plausible, this flaw makes it = more difficult to accept their results without equivocation. Last, but not least, Whelan and his collaborators conducted a meta-analysis= using published data from only those trials in which all patients were = treated with mastectomy plus axillary dissection and also received = systemic therapy, in which patients were randomized to receive postmastecto= my radiotherapy (PMRT) or not. This showed that PMRT reduced overall = mortality. (Of interest, they also found that this affect was lost in the = 3 trials in which PMRT was delayed by 6 months or more - a caution to the = increasing tendency to use longer chemotherapy regimens prior to starting = PMRT.) Because of the relative homogeneity of the surgical treatment, the = routine use of systemic therapy, and the use in may trials of radiotherapy = techniques similar to those employed now, this meta-analysis to me = therefore represents the strongest evidence for the role of radiotherapy = in improving survival. However, its weakness is the lack of sufficient = follow-up time in these trials to see potential late cardiac toxicity. I = have argued earlier in this Journal Club (December 1999) that the risk of = such complications is likely to be very small, if it exists at all. = Nonetheless, there are few studies of this problem in patients receiving = potentially cardiotoxic drugs, such as anthracyclines or Herceptin, and = there will be uncertainty on this issue for years to come. ******************=20 RES: Hoppe 10/00=20 AU: Oguchi M; Ikeda H; Isobe K; Hirota S; Hasegawa M; Nakamura K; Sasai K; = Hayabuchi N. TI: Tumor bulk as a prognostic factor for the management of localized = aggressive non-Hodgkin's lymphoma: a survey of the Japan Lymphoma = Radiation Therapy Group. SO: Int J Radiat Oncol Biol Phys 2000 Aug 1;48(1):161-8. Abstract: PURPOSE: To identify the prognostic factors that specifically predict = survival rates of patients with localized aggressive non-Hodgkin's = lymphoma (NHL). METHODS AND MATERIALS: The survey was carried out at 25 = radiation oncology institutions in Japan in 1998. The 5-year event-free = (EFS) and overall survival rates (OAS) were calculated, and univariate and = multivariate analyses were done to identify which of the following = factors, namely, gender, age, performance status (PS), serum lactate = dehydrogenase (LDH) level, Stage (I vs. II), tumor bulk (maximum diameter),= and treatment, were significant from the viewpoint of prognosis. RESULTS: = A total of 1141 patients with Stage I and II NHL were treated by the = Japanese Lymphoma Radiation Therapy Group between 1988 and 1992. Of them, = 787 patients, who were treated using definitive radiotherapy with or = without chemotherapy for intermediate- and high-grade lymphomas in working = formulation, constituted the core of this study. Primary tumors arose = mainly from extranodal organs (71%) in the head and neck (Waldeyer's = ring: 36% and sinonasal cavities: 9%). The factors associated with poorer = prognosis were age over 60 years old (p < 0. 0001), radiation therapy = alone (p < 0.0001), PS =3D 2-4 (p =3D 0.0011), (sex male, p =3D 0.0078), a = bulky tumor more than 6 cm in maximum diameter (p =3D 0.0088), elevated = LDH (p =3D 0.0117), and stage II (p =3D 0.0642). A median dose of 42 Gy = was delivered mainly to the involved fields. Short-course chemotherapy was = provided in 549 (70%) patients. The 5-year OAS and EFS rates for all = patients were 71% and 67%, respectively. According to the stage-modified = International Prognostic Index, the 5-year EFS of the patients with risk = factors from 0 to 1 was 76%, 61% for patients with two risk factors, and = 26% for patients with three or more risk factors. CONCLUSION: Extranodal = presentation, especially Waldeyer's ring and sinonasal cavities, is = encountered more frequently in Japan than in Western countries. Tumor bulk = is an important prognostic factor in patients with localized aggressive = extranodal NHL. Short course chemotherapy followed by radiation therapy = was associated with prolonged survival in patients with localized = aggressive NHLs of extranodal origin and 0-1 risk factor. Editor's comments: This is an interesting report of a large number of patients treated for = early stage aggressive lymphoma in Japan. It demonstrates the applicabilit= y of the International Prognostic Index for patients with early stage = disease. In addition, although the majority of patients were treated with = combined modality therapy, there is an interesting analysis of a cohort = treated with irradiation alone. In table 5, the results are displayed for = tumor size versus treatment. Although patients with disease <3cm = accounted for only about 10% of the patients, the 5-year EFS after = treatment with RT alone was 78% (vs. 76% for combined modality). There = are very few contemporary data regarding the role of RT alone in favorable = presentations of large cell lymphoma. The Princess Margaret Hospital = experience, reported by Sutcliffe et al. in 1985 identified a cohort of = patients (24% of the total) who were younger than 60, had stage I-IIA = localized, and small bulk (<5 cm) who had a 77% Relapse Free rate. The = Japanese and PMH data are similar and can be used as support for an RT = only approach in the setting of minimal disease, especially if there is = any contraindication or reluctance to employ chemotherapy. ******************=20 Lung/Mediastinum: Turrisi 10/00=20 No Reference Selected=20 ******************=20 GU: Roach 10/00=20 No Reference Selected ******************=20 Radiobiology: Withers 10/00=20 No Reference Selected ******************=20 Health Services Research: Hayman 10/00=20 AU: Earle CC; Chapman RH; Baker CS; Bell CM; Stone PW; Sandberg EA; = Neumann PJ. TI: Systematic overview of cost-utility assessments in oncology. SO: J Clin Oncol 2000 Sep 15;18(18):3302-17 URL: http://www.jco.org/cgi/content/abstract/18/18/3302 PDF: http://www.jco.org/cgi/reprint/18/18/3302 Abstract=20 PURPOSE: Cost-utility analyses (CUAs) present the value of an intervention = as the ratio of its incremental cost divided by its incremental survival = benefit, with survival weighted by utilities to produce quality-adjusted = life years (QALYs). We critically reviewed the CUA literature and its role = in informing clinical oncology practice, research priorities, and policy. = METHODS: The English-language literature was searched between 1975 and1997 = for CUAs. Two readers abstracted from each article descriptions of the = clinical situation and patients, the methods used, study perspective, the = measures of effectiveness, costs included, discounting, and whether = sensitivity analyses were performed. The readers then made subjective = quality assessments. We also extracted utility values from the reviewed = papers, along with information on how and from whom utilities were = measured. RESULTS: Our search yielded 40 studies, which described 263 = health states and presented 89 cost-utility ratios. Both the number and = quality of studies increased over time. However, many studies are at = variance with current standards. Only 20% of studies took a societal = perspective, more than a third failed to discount both the costs and = QALYs, and utilities were often simply estimates from the investigators or = other physicians. CONCLUSION: The cost-utility literature in oncology is = not large but is rapidly expanding. There remains much room for improvement= in the methodological rigor with which utilities are measured. Considering= quality-of-life effects by incorporating utilities into economic studies = is particularly important in oncology, where many therapies obtain modest = improvements in response or survival at the expense of nontrivial = toxicity. Editor's comments:=20 Although I know I have selected a number of review articles over the last = few months, I still think that this article is worth mentioning. Not only = does it include a review of several of the major issues associated with = performing cost-utility analyses but it also includes a listing of those = studies published in oncology prior to 1998 in which effectiveness was = assessed in quality-adjusted life-years or QALYs. For the uninitiated, = QALYs are an outcomes measure that allows for the incorporation of = quality, as well as quantity, of life through the use of a weighting = factor known as a utility. It has been recommended by the Panel on = Cost-Effectiveness in Health and Medicine (a group of experts convened by = the US Public Health Service to come up with guidelines for conducting and = reporting cost-effectiveness analyses) that effectiveness be measured in = the baseline analysis in QALYs, rather than for example in years of life = saved. The recommendations of the Panel have generally been accepted by = the health services research community (as well as by peer-reviewed = journals) and so we will be seeing more and more cost-utility analyses. = In many settings, the use of radiation has a greater impact on quality of = life than on survival (e.g., when administered for palliation, along with = chemotherapy for organ preservation, following surgery for local control, = etc.). Therefore, as a specialty, I believe that it will be increasingly = important for us to begin to measure utilities for the appropriate = outcomes so that we can appropriately assess the cost-effectiveness of the = use of radiation in these various settings. As this article points out, = very few cost-utility analyses have been published in oncology in the past = which focus primarily on radiation therapy (though several have been = published since 1998) and many of the utilities used in the older studies = examining other types of interventions were not measured using currently = accepted methods. It appears as if we have a lot of work to do! ******************=20 Radiation Biophysics: Chen 10/00=20 AU: Shirato H; Shimizu S; Kitamura K; Nishioka T; Kagei K; Hashimoto S; = Aoyama H; Kunieda T; Shinohara N; Dosaka-Akita H; Miyasaka K. TI: Four-dimensional treatment planning and fluoroscopic real-time tumor = tracking radiotherapy for moving tumor. SO: Int J Radiat Oncol Biol Phys 2000 Sep 1;48(2):435-42 Abstract: PURPOSE: To achieve precise three-dimensional (3D) conformal radiotherapy = for mobile tumors, a new radiotherapy system and its treatment planning = system were developed and used for clinical practice. METHODS AND = MATERIALS: We developed a linear accelerator synchronized with a fluoroscop= ic real-time tumor tracking system by which 3D coordinates of a 2.0-mm = gold marker in the tumor can be determined every 0.03 second. The 3D = relationships between the marker and the tumor at different respiratory = phases are evaluated using CT image at each respiratory phase, whereby the = optimum phase can be selected to synchronize with irradiation (4D = treatment planning). The linac is triggered to irradiate the tumor only = when the marker is located within the region of the planned coordinates = relative to the isocenter. RESULTS: The coordinates of the marker were = detected with an accuracy of +/- 1 mm during radiotherapy in the phantom = experiment. The time delay between recognition of the marker position and = the start or stop of megavoltage X-ray irradiation was 0.03 second. = Fourteen patients with various tumors were treated by conformal radiotherap= y with a "tight" planning target volume (PTV) margin. They were surviving = without relapse or complications with a median follow-up of 6 months. = CONCLUSION: Fluoroscopic real-time tumor tracking radiotherapy following = 4D treatment planning was developed and shown to be feasible to improve = the accuracy of the radiotherapy for mobile tumors. Editor's comments: It is hard to miss this article, since the equipment used is shown on the = front cover of the September issue of the Red Journal. Nevertheless, I = recommend this for reading because it is important to appreciate by how = much dose volume histograms could be degraded by respiration, and that = technology can be used to overcome organ motion and reduce margins. = Regrettably, the authors do not share in detail the recognition score = algorithms used to achieve a 1mm precision in gold marker localization, = but the descriptive material seems convincing. As pointed out, the chief = disadvantage is the insertion of an invasive marker, and the significant = expense in equipment. As the technology matures, it is clear that image = guided techniques will play a larger role in radiotherapy. ******************=20 Brian J. Goldsmith, M.D.=20 Moderator, IROJC From owner-radoncjc@net.bio.net Mon Oct 2 23:11:51 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 26F7817AB1; Mon, 2 Oct 2000 23:11:48 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 6028) id B72BC17A99; Mon, 2 Oct 2000 23:11:46 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 6024) id 48F9617A99; Mon, 2 Oct 2000 23:06:21 +0100 (BST) Received: from mail1.radiological.com (mail1.radiological.com [206.13.127.226]) by mercury.hgmp.mrc.ac.uk (Postfix) with SMTP id 13A71415D4 for ; Mon, 2 Oct 2000 23:06:19 +0100 (BST) Received: from RASROUTING-Message_Server by mail1.radiological.com with Novell_GroupWise; Mon, 02 Oct 2000 15:05:47 -0700 Message-Id: X-Mailer: Novell GroupWise 5.5.4 From: "Brian Goldsmith MD" To: Subject: Test October 2000 IROJC Content-Disposition: inline Newsgroups: bionet.radoncjc Date: Mon, 2 Oct 2000 23:11:46 +0100 (BST) Sender: owner-radoncjc@net.bio.net Precedence: bulk From: Brian Goldsmith MD To: Brian Goldsmith MD Date: 10/2/00 2:50PM Subject: October 2000 Internet Radiation Oncology Journal Club (IROJC) October 2000 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 65th 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 10/00 AU: Breneman JC; Wiener ES. TI: Issues in the local control of rhabdomyosarcoma. SO: Med Pediatr Oncol 2000 Aug;35(2):104-9. Abstract: BACKGROUND: Rhabdomyosarcoma (RMS) is a heterogeneous disease consisting of several different histologies arising from a variety of anatomic sites. Approximately half of the children who die of this tumor have failure at the primary site of involvement, making local control an important component of therapy. PROCEDURE: Published literature and newly analyzed data from the Intergroup Rhabdomyosarcoma Study Group (IRSG) regarding local control of RMS were reviewed. Information regarding the role of various local control modalities for different primary disease sites is presented along with new directions for clinical research. RESULTS: Local control rates for RMS average 80% for group III tumors, with large variations seen for different anatomic sites. Important gains in functional outcome for certain sites such as gynecologic system and bladder/prostate have been achieved by optimizing the use of the various treatment modalities. Local control at other sites such as the chest and extremities remains a problem. CONCLUSIONS: Advances in surgical and radiotherapy techniques coupled with multiagent chemotherapy are providing improved local control with decreasing morbidity. Optimal outcome is dependent on close collaboration between surgical, radiotherapy, and pediatric oncology specialists. Copyright 2000 Wiley-Liss, Inc. Editor's comments: The issues surrounding local control in Rhabdomyosarcoma are complex, and a function of site, age of the child, organ function/quality of life, and many many more. The Intergroup Rhabdomyosarcoma Study Group (IRSG) investigators are working to investigate these factors, clarify previous misunderstandings, and provide clinicians guidelines to consider when determining management/treatment approaches for individual patients. This article reviews many of the important aspects and is excellent reading for the Radiation Oncologist in practice who is trying to keep up with state of the art information, as well as the young resident/clinician who is trying to learn first hand a complex subject. Read and save this paper as excellent reference material. ****************** Head/Neck/Skin: Foote 10/00 AU: Davidson J; Gilbert R; Irish J; Witterick I; Brown D; Birt D; Freeman J; Gullane P. TI: The role of panendoscopy in the management of mucosal head and neck malignancy-A prospective evaluation. SO: Head Neck 2000 Aug;22(5):449-54. Abstract: BACKGROUND: It is common practice for a panendoscopy to be included in the evaluation of patients with mucosal head and neck malignancies. Whether this intervention is efficient or cost-effective has not been established in our patient population. METHODS: Two hundred twenty-four patients with squamous cell carcinoma involving the oral cavity, pharynx, larynx, or neck were evaluated prospectively with panendoscopy and chest x-ray with or without barium swallow. One hundred fifty-four patients had newly diagnosed tumors and 70 were previously diagnosed and currently undergoing symptom-directed investigations. RESULTS: The incidence of synchronous primary tumors was 2.6% (4 of 154); pulmonary, 1.3%; head and neck mucosa, 1.3%; and esophageal, 0%. There was no associated morbidity. CONCLUSIONS: Although there was no associated morbidity, our head and neck oncology group is of the opinion that routine panendoscopy is not warranted. Specific indications for this investigation are discussed. Copyright 2000 John Wiley & Sons, Inc. Head Neck 22: 449-455, 2000. ****************** GYN: Petereit 10/00 AU: Grogan M; Thomas GM; Melamed I; Wong FL; Pearcey RG; Joseph PK; Portelance L; Crook J; Jones KD. TI: The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. SO: Cancer 1999 Oct 15;86(8):1528-36. URL: http://canceronline.wiley.com/cgi-bin/abstracts/v86n8/v86n8p1528.abstract.html PDF: http://canceronline.wiley.com/server-java/Arknoid/cancer/0008-543X/v86n8/v86n8p1528-frameset.html Abstract: BACKGROUND: It is unclear whether blood transfusion can overcome the negative impact of anemia before or during radiotherapy (RT) in patients with carcinoma of the cervix. The objective of this retrospective study was to examine the impact of anemia and blood transfusion on 605 patients with carcinoma of the cervix treated with radical RT at 7 centers across Canada in 1989, 1990, and 1992. METHODS: The data collected included hemoglobin (Hgb) levels from the time of diagnosis to the end of therapy; blood transfusions administered; and identifiable patient-, tumor-, and treatment-related factors. Survival, disease free survival, and pelvic control analyses were evaluated by univariate and multivariate analysis. RESULTS: The median follow-up was 41 months (range, 0-92 months). Presenting Hgb level, average weekly nadir Hgb (AWNH) during RT, and blood transfusion were correlated significantly with local control, disease free survival, and overall survival on univariate analysis. However, the AWNH remained significant on multivariate analysis, whereas Hgb at presentation and blood transfusion did not. The 5-year survival was 74% for patients with an AWNH >/= 120 g/L, 52% for patients with AWNH levels 110-119 g/L inclusive, and 45% for patients with AWNH levels < 110 g/L (P < 0.0001). At each Hgb level, patients who were transfused and maintained a specific Hgb level had a survival rate that was not significantly different from patients who were at that level spontaneously. There was a significant reduction in both pelvic and distant recurrence (P < 0.0001 and P < 0.0006, respectively) in patients whose AWNH level during RT was >/= 120 g/L compared with < 120 g/L. A reduction in the rate of distant recurrence was observed in patients with and without pelvic recurrence. CONCLUSIONS: AWNH is highly predictive of outcome for patients treated with RT for carcinoma of the cervix. Blood transfusion appears to overcome the negative prognostic effects of low presenting Hgb levels and AWNH levels. Copyright 1999 American Cancer Society. Editor's comments: A retrospective study from seven Canadian cancer centers investigated the importance of anemia and impact of blood transfusions in cervical patients who underwent radical radiotherapy. Hemoglobin data was collected in approximately 600 patients: presenting Hgb level, average weekly nadir Hgb (AWNH) and post-transfusion Hgb levels-all endpoints were correlated to pelvic control and survival. The following intriguing results were found: 1) 12% decrease in survival for patients with a Hgb level < 12.0 g/l vs > 12.0 g/l 2) AWNH levels correlated to survival and pelvic control on multivariate analysis-second only to tumor stage 3) a stepwise increase in survival for each AWNH achieved up to 12.0 g/l for transfused and non-transfused patients. At each Hgb level, transfused patients had the same outcome as patients who spontaneously achieved the same Hgb level. 4) The positive impact of transfusions was further studied by subdividing patients into four groups: high vs low Hgb levels (< vs > 12.0 g/l) and the impact of transfusions. Patients who presented with a low Hgb level and were raised to a high level during radiation had outcomes comparable to those patients who presented and maintained a high Hgb level. 5) The worst outcome was observed for those patients who presented with a high Hgb level which subsequently fell during radiotherapy. 6) For patients with a high Hgb level, both the pelvic and distant failure rates were lower. Grogan and Thomas present an excellent discussion of their results, including implications for current practice and future trials. They suggest keeping the Hgb level above 12.0 g/l during radiotherapy. Their data strongly suggests that transfusing these patients to a level above 12.0 g/l and maintaining that level, will potentially overcome the negative effects of anemia. ****************** GI / Soft Tissue Sarcoma: Tepper 10/00 No Reference Selected ****************** CNS: Bauman 10/00 AU: Abrey LE; Yahalom J; DeAngelis LM. TI: Treatment for primary CNS lymphoma: the next step. SO: J Clin Oncol 2000 Sep;18(17):3144-50 URL: http://www.jco.org/cgi/content/abstract/18/17/3144 PDF: http://www.jco.org/cgi/reprint/18/17/3144 Abstract: PURPOSE: The use of preradiotherapy (RT) methotrexate (MTX) has improved disease control and survival in patients with primary CNS lymphoma (PCNSL). The reported protocol was designed to optimize and enhance the chemotherapeutic component of treatment. PATIENTS AND METHODS: Fifty-two patients were treated with five cycles of high-dose MTX 3.5 g/m(2), procarbazine 100 mg/m(2)/d, and vincristine 1.4 mg/m(2). Thirty patients received whole-brain RT (45 Gy). Twenty-two older patients deferred RT to diminish the risk of delayed neurotoxicity; these patients are compared with 12 older patients who completed the entire treatment regimen. Most patients (n = 35) received high-dose cytarabine after RT. RESULTS: Objective response rate to the induction chemotherapy regimen was 90%; overall median survival is 60 months. Grade 3 or 4 myelosuppression was seen in 30 patients, primarily in association with cytarabine; grade 3 nephrotoxicity due to MTX was seen in two patients. Older patients had similar median survival with or without the addition of RT: 32 versus 33 months, respectively. However, late neurotoxicity was significantly more common in those older patients who received RT (P: =.00004). Patients younger than 60 years who received the complete treatment regimen have not reached median disease-free or overall survival. CONCLUSION: Increasing the dose of MTX and adding procarbazine and vincristine improved disease control and overall survival in patients with newly diagnosed PCNSL. Younger patients in particular fared extremely well with this treatment regimen. In older patients, deferring whole-brain RT did not compromise overall survival but did reduce treatment-related toxicity. Editor's comments: Non-randomized studies of chemotherapy combinations similar to that of the DeAngelis regimen added to cranial radiation suggest significantly improved survival compared to cranial radiation alone. A recent case control study reported at ASCO (Schultz, C., Scott, C., DeAngelis, L., Nelson, D., Nelson, J., Schold, S.and Curran, W.: Radiation Therapy (RT) Alone Vs. Pre-RT Chemotherapy (CTX) for the Treatment of Primary CNS Lymphoma(PCNSL): Aged Matched Survival Analysis of RTOG 83-15 and RTOG 93-10. Proc of Am Soc Clin Oncol (ASCO), New Orleans, LA, J Clin Oncol, 19 159a, 2000) confirms the apparent benefit of (neo)adjuvant chemotherapy. The toxicity of combined chemo-radiation can be considerable in older (>60) patients as noted by DeAngelis. DeAngelis' work suggests that chemotherapy alone may be of equivalent palliative benefit in this group with less toxicity. Caution needs to be exercised in this conclusion as the groups were not randomized and formal neuropsychologic testing was not performed. Also, all the younger patients received combined modality. CNS lymphoma trials in development through the RTOG propose to compare deferred vs immediate radiation in patients with a CR to induction chemotherapy. Randomized trials such as these are necessary to confirm the safety and efficacy of "de-escalation" of therapy by ommission of the cranial radiation. Also, what about the older patient who does not/will not tolerate chemotherapy or has a poor radiographic response to chemotherapy? Cranial radiation may still be necessary in this group, despite the potential toxicity.... ****************** Breast: Recht 10/00 TI: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. SO: Lancet 2000 May 20;355(9217):1757-70. URL: http://www.thelancet.com/newlancet/sub/issues/vol355no9217/article1757.html Abstract: BACKGROUND: The long-term effects of radiotherapy on mortality from breast cancer and other causes remain uncertain. METHODS: A meta-analysis was done of 10-year and 20-year results from 40 unconfounded randomised trials of radiotherapy for early breast cancer. It involved central review of individual patients' data on recurrence and cause-specific mortality from 20000 women, half with "node-positive" disease. Radiotherapy fields generally included not only chest wall (or breast) but also axillary, supraclavicular, and internal mammary nodes. FINDINGS: A reduction of approximately two-thirds in local recurrence was seen in all trials, largely independent of the type of patient or type of radiotherapy (8.8% vs 27.2% local recurrence by year 10). Hence, to assess effects on breast cancer mortality of substantially better local control, results from all trials were combined. Breast cancer mortality was reduced (2p=0.0001) but other, particularly vascular, mortality was increased (2p=0.0003), and overall 20-year survival was 37.1% with radiotherapy versus 35.9% control (2p=0.06). There was little effect on early deaths, but logrank analyses of later deaths indicate that, on average after year 2, radiotherapy reduced annual mortality rates from breast cancer by 13.2% (SE 2.5) but increased those from other causes by 21.2% (SE 5.4). Nodal status, age, and decade of follow-up strongly affected the ratio of breast cancer mortality to other mortality, and hence affected the ratio of absolute benefit to absolute hazard from these proportional changes in mortality. INTERPRETATION: Radiotherapy regimens able to produce the two-thirds reduction in local recurrence seen in these trials, but without long-term hazard, would be expected to produce an absolute increase in 20-year survival of about 2-4% (except for women at particularly low risk of local recurrence). The average hazard seen in these trials would, however, reduce this 20-year survival benefit in young women and reverse it in older women. AND AU: Van de Steene J; Soete G; Storme G. TI: Adjuvant radiotherapy for breast cancer significantly improves overall survival: the missing link. SO: Radiother Oncol 2000 Jun;55(3):263-72. Abstract: Background and purpose: The influence of surgical adjuvant radiotherapy on overall survival of patients with operable breast cancer is still a controversial subject. The negative result of the EBCTCG meta-analysis (Early breast cancer trialists', collaborative group. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomised trials. N. Engl. J. Med. 1995;333:1444-1455) of clinical randomized trials on adjuvant radiotherapy in breast cancer is in strong contrast with the Danish 82B, 82C and British Columbia trials (Overgaard M, Hanse PS, Overgaar J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N. Engl. J. Med. 1997;337:949-955; Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomized trial. Lancet 1999;353:1641-1648; Ragaz J, Jackson S, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N. Engl. J. Med. 1997;337:956-962) showing an impressive survival benefit. This paper tries to fill in the gap between the conflicting results. Materials and methods: The 36 trials of the EBCTCG (Early breast cancer trialists', collaborative group, 1995) were prospectively screened for a number of objective parameters that are usually not analyzed in review papers. The odds of death data (and its variance) were borrowed from the original meta-analysis (Early breast cancer trialists', collaborative group, 1995) to check whether the objective features were significant predictors for overall survival benefit.Results: A significant survival benefit for the radiotherapy arm was found for recent trials (2P<0.05), large trials (2P<0.03), trials that used standard fractionation (2P<0.02), and trials with a favourable crude survival (2P<0.03). For these four parameters clear parameter-effect relations were found. In recent and large trials the odds reduction was 12.4% (2P=0.004).Conclusions: Surgical adjuvant radiotherapy significantly improves overall survival of breast cancer patients provided that current techniques are used and treatment is given with standard fractionation. For the best subgroups we observed an odds of death reduction of more than 20%. The results of this study stress the importance of reducing cardiovascular and other late toxicity in adjuvant radiotherapy for breast cancer. AND AU: Whelan TJ; Julian J; Wright J; Jadad AR; Levine ML. TI: Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. SO: J Clin Oncol 2000 Mar;18(6):1220-9. URL: http://www.jco.org/cgi/content/abstract/18/6/1220 PDF: http://www.jco.org/cgi/reprint/18/6/1220 Abstract: PURPOSE: Recent randomized trials in women with node-positive breast cancer who received systemic treatment report that locoregional radiation therapy improves survival. Previous trials failed to detect a difference in survival that results from its use. A systematic review of randomized trials that examine the effectiveness of locoregional radiation therapy in patients treated by definitive surgery and adjuvant systemic therapy was conducted. METHODS: Randomized trials published between 1967 and 1999 were identified through MEDLINE database, CancerLit database, and reference lists of relevant articles. Relevant data was abstracted. The results of randomized trials were pooled using meta-analyses to estimate the effect of treatment on any recurrence, locoregional recurrence, and mortality. RESULTS: Eighteen trials that involved a total of 6,367 patients were identified. Most trials included both pre- and postmenopausal women with node-positive breast cancer treated with modified radical mastectomy. The type of systemic therapy received, sites irradiated, techniques used, and doses of radiation delivered varied between trials. Data on toxicity were infrequently reported. Radiation was shown to reduce the risk of any recurrence (odds ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.83), local recurrence (odds ratio, 0.25; 95% CI, 0.19 to 0.34), and mortality (odds ratio, 0.83; 95% CI, 0.74 to 0.94). CONCLUSION: Locoregional radiation after surgery in patients treated with systemic therapy reduced mortality. Several questions remain on how these results should be translated into current-day clinical practice. Editor's comments: The role of radiotherapy in reducing mortality from breast cancer and increasing overall survival rates has been debated for decades. Numerous randomized trials have shown that radiotherapy substantially reduces the risk of local-regional failure, but trial results with regards to these two other endpoints have been mixed. There have been few meta-analyses performed of these trials. The best-known and most influential have been those of the The Early Breast Cancer Trialists' Collaborative Group. The most recent of these did not show an advantage in overall survival at 20 years for patients receiving radiotherapy following surgery, compared to those who did not. While there was a statistically-significant reduction in the risk of breast-cancer related deaths, this was counterbalanced by an increase in the risk of non-breast cancer mortality (mainly cardiovascular, although the cause of death was not known for many patients), particularly in women over age 50. However, this analysis included trials in which breast-conserving surgery, simple mastectomy, or radical mastectomy, as well as modified radical mastectomy, were used. Patients with both positive and negative axillary nodes were included. Many of the trials employed outdated radiotherapy techniques, such as the use of orthovoltage equipment. Most importantly, this study did not segregate trials in which systemic therapy was routinely given to patients from those in which systemic therapy was not used. Finally, many of the older trials in particular used fraction sizes in excess of 2 Gy, which likely amplified the risk of cardiac complications substantially, especially when combined with older treatment techniques. Unfortunately, the subgroup analyses performed did not segregate these important factors. Thus, the value of this overview for settling this debate is limited. The meta-analysis from van de Steene and colleagues attempts to rectify some of these problems by performing the critical subgroup analyses using information from the 1995 Oxford overview (N Engl J Med 1995;353:1641-8). However, this effort did not segregate the trials according to the type of surgery (e.g., mastectomy with axillary dissection versus breast-conserving therapy). Although their conclusions are plausible, this flaw makes it more difficult to accept their results without equivocation. Last, but not least, Whelan and his collaborators conducted a meta-analysis using published data from only those trials in which all patients were treated with mastectomy plus axillary dissection and also received systemic therapy, in which patients were randomized to receive postmastectomy radiotherapy (PMRT) or not. This showed that PMRT reduced overall mortality. (Of interest, they also found that this affect was lost in the 3 trials in which PMRT was delayed by 6 months or more - a caution to the increasing tendency to use longer chemotherapy regimens prior to starting PMRT.) Because of the relative homogeneity of the surgical treatment, the routine use of systemic therapy, and the use in may trials of radiotherapy techniques similar to those employed now, this meta-analysis to me therefore represents the strongest evidence for the role of radiotherapy in improving survival. However, its weakness is the lack of sufficient follow-up time in these trials to see potential late cardiac toxicity. I have argued earlier in this Journal Club (December 1999) that the risk of such complications is likely to be very small, if it exists at all. Nonetheless, there are few studies of this problem in patients receiving potentially cardiotoxic drugs, such as anthracyclines or Herceptin, and there will be uncertainty on this issue for years to come. ****************** RES: Hoppe 10/00 AU: Oguchi M; Ikeda H; Isobe K; Hirota S; Hasegawa M; Nakamura K; Sasai K; Hayabuchi N. TI: Tumor bulk as a prognostic factor for the management of localized aggressive non-Hodgkin's lymphoma: a survey of the Japan Lymphoma Radiation Therapy Group. SO: Int J Radiat Oncol Biol Phys 2000 Aug 1;48(1):161-8. Abstract: PURPOSE: To identify the prognostic factors that specifically predict survival rates of patients with localized aggressive non-Hodgkin's lymphoma (NHL). METHODS AND MATERIALS: The survey was carried out at 25 radiation oncology institutions in Japan in 1998. The 5-year event-free (EFS) and overall survival rates (OAS) were calculated, and univariate and multivariate analyses were done to identify which of the following factors, namely, gender, age, performance status (PS), serum lactate dehydrogenase (LDH) level, Stage (I vs. II), tumor bulk (maximum diameter), and treatment, were significant from the viewpoint of prognosis. RESULTS: A total of 1141 patients with Stage I and II NHL were treated by the Japanese Lymphoma Radiation Therapy Group between 1988 and 1992. Of them, 787 patients, who were treated using definitive radiotherapy with or without chemotherapy for intermediate- and high-grade lymphomas in working formulation, constituted the core of this study. Primary tumors arose mainly from extranodal organs (71%) in the head and neck (Waldeyer's ring: 36% and sinonasal cavities: 9%). The factors associated with poorer prognosis were age over 60 years old (p < 0. 0001), radiation therapy alone (p < 0.0001), PS = 2-4 (p = 0.0011), (sex male, p = 0.0078), a bulky tumor more than 6 cm in maximum diameter (p = 0.0088), elevated LDH (p = 0.0117), and stage II (p = 0.0642). A median dose of 42 Gy was delivered mainly to the involved fields. Short-course chemotherapy was provided in 549 (70%) patients. The 5-year OAS and EFS rates for all patients were 71% and 67%, respectively. According to the stage-modified International Prognostic Index, the 5-year EFS of the patients with risk factors from 0 to 1 was 76%, 61% for patients with two risk factors, and 26% for patients with three or more risk factors. CONCLUSION: Extranodal presentation, especially Waldeyer's ring and sinonasal cavities, is encountered more frequently in Japan than in Western countries. Tumor bulk is an important prognostic factor in patients with localized aggressive extranodal NHL. Short course chemotherapy followed by radiation therapy was associated with prolonged survival in patients with localized aggressive NHLs of extranodal origin and 0-1 risk factor. Editor's comments: This is an interesting report of a large number of patients treated for early stage aggressive lymphoma in Japan. It demonstrates the applicability of the International Prognostic Index for patients with early stage disease. In addition, although the majority of patients were treated with combined modality therapy, there is an interesting analysis of a cohort treated with irradiation alone. In table 5, the results are displayed for tumor size versus treatment. Although patients with disease <3cm accounted for only about 10% of the patients, the 5-year EFS after treatment with RT alone was 78% (vs. 76% for combined modality). There are very few contemporary data regarding the role of RT alone in favorable presentations of large cell lymphoma. The Princess Margaret Hospital experience, reported by Sutcliffe et al. in 1985 identified a cohort of patients (24% of the total) who were younger than 60, had stage I-IIA localized, and small bulk (<5 cm) who had a 77% Relapse Free rate. The Japanese and PMH data are similar and can be used as support for an RT only approach in the setting of minimal disease, especially if there is any contraindication or reluctance to employ chemotherapy. ****************** Lung/Mediastinum: Turrisi 10/00 No Reference Selected ****************** GU: Roach 10/00 No Reference Selected ****************** Radiobiology: Withers 10/00 No Reference Selected ****************** Health Services Research: Hayman 10/00 AU: Earle CC; Chapman RH; Baker CS; Bell CM; Stone PW; Sandberg EA; Neumann PJ. TI: Systematic overview of cost-utility assessments in oncology. SO: J Clin Oncol 2000 Sep 15;18(18):3302-17 URL: http://www.jco.org/cgi/content/abstract/18/18/3302 PDF: http://www.jco.org/cgi/reprint/18/18/3302 Abstract PURPOSE: Cost-utility analyses (CUAs) present the value of an intervention as the ratio of its incremental cost divided by its incremental survival benefit, with survival weighted by utilities to produce quality-adjusted life years (QALYs). We critically reviewed the CUA literature and its role in informing clinical oncology practice, research priorities, and policy. METHODS: The English-language literature was searched between 1975 and1997 for CUAs. Two readers abstracted from each article descriptions of the clinical situation and patients, the methods used, study perspective, the measures of effectiveness, costs included, discounting, and whether sensitivity analyses were performed. The readers then made subjective quality assessments. We also extracted utility values from the reviewed papers, along with information on how and from whom utilities were measured. RESULTS: Our search yielded 40 studies, which described 263 health states and presented 89 cost-utility ratios. Both the number and quality of studies increased over time. However, many studies are at variance with current standards. Only 20% of studies took a societal perspective, more than a third failed to discount both the costs and QALYs, and utilities were often simply estimates from the investigators or other physicians. CONCLUSION: The cost-utility literature in oncology is not large but is rapidly expanding. There remains much room for improvement in the methodological rigor with which utilities are measured. Considering quality-of-life effects by incorporating utilities into economic studies is particularly important in oncology, where many therapies obtain modest improvements in response or survival at the expense of nontrivial toxicity. Editor's comments: Although I know I have selected a number of review articles over the last few months, I still think that this article is worth mentioning. Not only does it include a review of several of the major issues associated with performing cost-utility analyses but it also includes a listing of those studies published in oncology prior to 1998 in which effectiveness was assessed in quality-adjusted life-years or QALYs. For the uninitiated, QALYs are an outcomes measure that allows for the incorporation of quality, as well as quantity, of life through the use of a weighting factor known as a utility. It has been recommended by the Panel on Cost-Effectiveness in Health and Medicine (a group of experts convened by the US Public Health Service to come up with guidelines for conducting and reporting cost-effectiveness analyses) that effectiveness be measured in the baseline analysis in QALYs, rather than for example in years of life saved. The recommendations of the Panel have generally been accepted by the health services research community (as well as by peer-reviewed journals) and so we will be seeing more and more cost-utility analyses. In many settings, the use of radiation has a greater impact on quality of life than on survival (e.g., when administered for palliation, along with chemotherapy for organ preservation, following surgery for local control, etc.). Therefore, as a specialty, I believe that it will be increasingly important for us to begin to measure utilities for the appropriate outcomes so that we can appropriately assess the cost-effectiveness of the use of radiation in these various settings. As this article points out, very few cost-utility analyses have been published in oncology in the past which focus primarily on radiation therapy (though several have been published since 1998) and many of the utilities used in the older studies examining other types of interventions were not measured using currently accepted methods. It appears as if we have a lot of work to do! ****************** Radiation Biophysics: Chen 10/00 AU: Shirato H; Shimizu S; Kitamura K; Nishioka T; Kagei K; Hashimoto S; Aoyama H; Kunieda T; Shinohara N; Dosaka-Akita H; Miyasaka K. TI: Four-dimensional treatment planning and fluoroscopic real-time tumor tracking radiotherapy for moving tumor. SO: Int J Radiat Oncol Biol Phys 2000 Sep 1;48(2):435-42 Abstract: PURPOSE: To achieve precise three-dimensional (3D) conformal radiotherapy for mobile tumors, a new radiotherapy system and its treatment planning system were developed and used for clinical practice. METHODS AND MATERIALS: We developed a linear accelerator synchronized with a fluoroscopic real-time tumor tracking system by which 3D coordinates of a 2.0-mm gold marker in the tumor can be determined every 0.03 second. The 3D relationships between the marker and the tumor at different respiratory phases are evaluated using CT image at each respiratory phase, whereby the optimum phase can be selected to synchronize with irradiation (4D treatment planning). The linac is triggered to irradiate the tumor only when the marker is located within the region of the planned coordinates relative to the isocenter. RESULTS: The coordinates of the marker were detected with an accuracy of +/- 1 mm during radiotherapy in the phantom experiment. The time delay between recognition of the marker position and the start or stop of megavoltage X-ray irradiation was 0.03 second. Fourteen patients with various tumors were treated by conformal radiotherapy with a "tight" planning target volume (PTV) margin. They were surviving without relapse or complications with a median follow-up of 6 months. CONCLUSION: Fluoroscopic real-time tumor tracking radiotherapy following 4D treatment planning was developed and shown to be feasible to improve the accuracy of the radiotherapy for mobile tumors. Editor's comments: It is hard to miss this article, since the equipment used is shown on the front cover of the September issue of the Red Journal. Nevertheless, I recommend this for reading because it is important to appreciate by how much dose volume histograms could be degraded by respiration, and that technology can be used to overcome organ motion and reduce margins. Regrettably, the authors do not share in detail the recognition score algorithms used to achieve a 1mm precision in gold marker localization, but the descriptive material seems convincing. As pointed out, the chief disadvantage is the insertion of an invasive marker, and the significant expense in equipment. As the technology matures, it is clear that image guided techniques will play a larger role in radiotherapy. ****************** Brian J. Goldsmith, M.D. Moderator, IROJC