From daemon Mon Dec 6 13:56:22 1999 Received: (from daemon@localhost) by net.bio.net (8.9.1a/8.9.1) id NAA22909; Mon, 6 Dec 1999 13:56:22 -0800 (PST) Message-Id: <199912062156.NAA22909@net.bio.net> To: radoncjc@net.bio.net Subject: December 1999 Internet Radiation Oncology Journal Club (IROJC) Reply-To: radoncjc@net.bio.net Date: Mon, 06 Dec 1999 16:32:57 -0500 From: Brian Goldsmith December 1999 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 55th 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 ----------------------------------------------------- You're encouraged to critically review this set of references and respond by posting your comments to the IROJC readership at radoncjc@net.bio.net. Comments should be in compliance with IROJC commentary rules (see below). In the month that follows this posting of references, submitted comments will be delivered to the e-mail boxes of the IROJC readership, with the goal of stimulating a professional discussion of these references and their subjects. ------------------------------------------------------------ ARCHIVED IROJC POSTINGS and commentary are available on the World Wide Web! Look for them on http://www.bio.net/ Click on the "Access the BIOSCI/bionet Newsgroups" hyperlink, and then go to "RADIATION-ONCOLOGY/Prototype". Or directly access the RADIATION-ONCOLOGY folder at http://www.bio.net/hypermail/RADIATION-ONCOLOGY/ There's also a freeWAIS search tool at the website, for searching archived postings for keywords or phrases! ------------------------------------------------------------ Commentary Rules: (1) Please cite the subject category in the header of your e-mail message, e.g., Subject: CNS 12/99. (2) Address the readership at large - not the Editor who suggested the reference. The Editor is under no obligation to respond to questions posed by the IROJC readership. (3) The Editor's selection is not necessarily an endorsement of the authors' conclusions. In fact, articles may be selected for criticism. (4) Comments posted to the Internet are public. Professional wording is prudent. (5) Comment only on journal articles that you have read recently, and please keep comments specific. (6) In order to minimize confusion, limit comments to the current month's list of references. (7) Please sign all comments and questions to the IROJC. By identifying yourself, you promote a more collegial and friendly environment! (8) Address to the Moderator (briandeb@bellatlantic.net) private questions and comments which are not intended for IROJC posting and public reading. ****************** Peds: Donaldson 12/99 AU: Wolden SL; Anderson JR; Crist WM; Breneman JC; Wharam MD Jr; Wiener ES; Qualman SJ; Donaldson SS. TI: Indications for Radiotherapy and Chemotherapy After Complete Resection in Rhabdomyosarcoma: A Report From the Intergroup Rhabdomyosarcoma Studies I to III. SO: J Clin Oncol 1999 Nov;17(11):3468-3475. URL: http://www.jco.org/cgi/content/full/17/11/3468 PDF: http://www.jco.org/cgi/reprint/17/11/3468 Abstract: PURPOSE: To evaluate the outcome of patients with rhabdomyosarcoma (RMS) treated with complete surgical resection and multiagent chemotherapy, with or without local radiotherapy (RT). PATIENTS AND METHODS: Four hundred thirty-nine patients with completely resected (ie, group I) RMS were further treated with chemotherapy (vincristine and actinomycin D ± cyclophosphamide, doxorubicin, and cisplatin) on Intergroup Rhabdomyosarcoma Studies (IRS) I to III between 1972 and 1991. Eighty-three patients (19%) also received local RT as a component of initial treatment. RESULTS: Eighty-six patients relapsed (10-year failure-free survival [FFS] 79%, overall survival 89%). Six percent of failure sites were local, 6% were regional, and 7% were distant. Poor prognostic factors were tumor size greater than 5 cm, alveolar or undifferentiated histology, primary tumor sites other than genitourinary, and treatment on IRS-I or II. For patients with embryonal RMS who were treated with RT, there was a trend for improved FFS but no difference in overall survival. On IRS-I and II, patients with alveolar or undifferentiated sarcoma who received RT compared with those who did not receive RT had greater 10-year FFS rates (73% v 44%, respectively; P equals .03) and overall survival rates (82% v 52%, respectively; (P equals .02). Such patients who received RT on IRS III also benefited more than those who did not receive RT (10-year FFS, 95% v 69%; P equals .01; overall survival, 95% v 86%; P equals .23). CONCLUSION: Patients with group I embryonal RMS have an excellent prognosis when treated with adjuvant multiagent chemotherapy without RT. Patients with alveolar RMS or undifferentiated sarcoma fare worse; however, FFS and overall survival are substantially improved when RT is added to multiagent chemotherapy (IRS-I and II). The best outcome occurred in IRS-III, when RT was used in conjunction with intensified chemotherapy. Editor's comments: It is not often when a retrospective clinical research project reveals findings so major as to change the practice of radiation oncology around the world. However this paper by Wolden and IRSG investigators describes such an observation. The notion has often been advanced that children with rhabdomyosarcoma who have an initial complete resection and who receive chemotherapy, do not need local irradiation. In fact, surgeons have used this argument as justification of doing an initial major surgical procedure, even initial amputation, saying that if the limb is removed there is no risk of local failure! Wolden et al. have now shown quite conclusively and convincingly that patients with Group I (completely resected disease), who have unfavorable histology (Alveolar and/or Undifferentiated tumors), have an unacceptably high risk of local/regional failure. Furthermore they have shown that this high failure risk can be reduced using radiation therapy. In addition overall outcome as measured by Failure Free Survival and Overall Survival is also improved among those patients who were irradiated in addition to receiving chemotherapy plus surgery. These findings have now resulted in the recommendation for routine radiotherapy (36 Gy) in all patients with completely resected rhabdomyosarcoma of the alveolar or undifferentiated histologic subtype. Patients with completely resected tumors of embryonal histology do not need initial routine radiotherapy. Patients with microscopic residual disease, nodal disease, or grossly resected disease of either embryonal, alveolar, or undifferentiated histology are recommended to receive differing radiotherapy doses. Interested readers should consult the IRSG protocol guidelines for more details. ****************** Head/Neck/Skin: Foote 12/99 AU: Eisbruch A; Ten Haken RK; Kim HM; Marsh LH; Ship JA. TI: Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. SO: Int J Radiat Oncol Biol Phys 1999 Oct 1;45(3):577-87. Abstract: PURPOSE: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). METHODS AND MATERIALS: Eighty-eight patients with head and neck cancer irradiated with parotid- sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose-volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman- Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to less than or equal to 25% pre-RT flow at 12 months. RESULTS: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) equals 28.4 Gy, n (volume dependence parameter) equals 1, and m (the slope of the dose/response relationship) equals 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. CONCLUSIONS: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of less than or equal to 26 Gy should be a planning goal if substantial sparing of the gland function is desired. ****************** GYN: Petereit 12/99 AU: Sedlis A; Bundy BN; Rotman MZ; Lentz SS; Muderspach LI; Zaino RJ. TI: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. SO: Gynecol Oncol 1999 May;73(2):177-83. Abstract: OBJECTIVE: The objective of this study was to evaluate the benefits and risk of adjuvant pelvic radiotherapy aimed at reducing recurrence in women with Stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. METHODS: Two hundred seventy-seven eligible patients were entered with at least two of the following risk factors: greater than 1/3 stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Of 277 patients, 137 were randomized to pelvic radiotherapy (RT) and 140 to no further treatment (NFT). RESULTS: Twenty-one (15%) in the RT group and 39 (28%) in the NFT group had a cancer recurrence, 18 of whom were vaginal/pelvic in the RT and 27 in the NFT group. In the RT group, of 18 (13%) who died, 15 died of cancer. In the NFT group, of the 30 (21%) who died, 25 died from cancer. Life table analysis indicated a statistically significant (47%) reduction in risk of recurrence (relative risk equals 0.53, P equals 0.008, one- tail) among the RT group, with recurrence-free rates at 2 years of 88% versus 79% for the RT and NFT groups, respectively. Severe or life- threatening (Gynecologic Oncology Group grade 3 or 4) urologic adverse effects occurred in 4 (3.1%) in the RT group and 2 (1.4%) in the NFT group; 3 (2.3%) and 1 (0.7%) hematologic; 4 (3.1%) and 0 gastrointestinal (GI); and 1 (0.8%) and 0 neurologic, respectively. One patient's death was attributable to grade 4 GI adverse effects. CONCLUSIONS: Adjuvant pelvic radiotherapy following radical surgery reduces the number of recurrences in women with Stage IB cervical cancer at the cost of 6% grade 3/4 adverse events versus 2.1% in the NFT group. Copyright 1999 Academic Press. Editor's comments: Sedlis et al. recently reported a reduction in the recurrence rates for high-risk stage IB cervical patients who were randomized to adjuvant pelvic radiotherapy after surgery (88% versus 79% -- GOG #92). Patients in this study were deemed to have a 30% risk of recurrence post-operatively based on a previous GOG study (GOG #49) [Delgado et al. Gyn Oncol 38:352-357;1990]. All patients had negative lymph nodes, but high-risk central features. Patients randomized to adjuvant radiotherapy received either 46 Gy in 23 fractions or 50.4 Gy in 28 fractions -- no patients received a brachytherapy boost. At 2 years, 21% of the surgery alone patients failed, compared to 12% of those radiated. The survival rates at 2 years were 79% in the surgery arm and 87% in the radiation arm -- P value not significant. Pelvic recurrences occurred in 21% of patients observed and 13% of patients radiated. Significant complications (grade 3/4) were encountered in 6% of the radiated patients and 2% of the observed patients. It is important to note that about 7% of patients randomized to radiation refused it, 11% were non-compliant and received less than 85% of the prescribed dose, and 20% had treatment times in excess of the planned treatment time. Thus, 1 out of 6 patients received less than optimal or no radiotherapy!!! This may help explain the disappointing pelvic control rates after surgery and radiation. Additional factors include missing the target volume and omission of vaginal brachytherapy. Two to three members of the cervix committee in the GOG are currently reviewing port films to assess the probability of a geographic miss. It is amazing that any benefit was observed with radiotherapy when considering the above factors! So what is the take home message? Should patients who fit these criteria for high-risk central features receive post-operative radiotherapy? Interestingly, 64% of patients entered on this trial had tumors greater than 4 cm. The randomized trial from Italy, demonstrated similar survival and relapse-free survival rates when comparing surgery (most had post-operative radiotherapy because of large tumor size) to primary radiotherapy. Unfortunately, 28% of the patients that received post-operative radiotherapy suffered serious late complications compared to 12% of those who received radiation alone [Landoni et al. Lancet 350:535-540,1997]. These higher complications observed for dual-therapy were much higher, and possibly more realistic, than that reported in the current Sedlis trial -- relatively short follow-up, only two years. My own bias is that the Sedlis study is helpful for assessing the value of post-operative radiotherapy for stage IB-I tumors (less than 4 cm) who have these high-risk central features. Patients who have tumors greater than 4 cm (IB-2 and above) should receive primary radiotherapy and not surgery. It is a step backwards to be managing woman with large tumors with surgery and radiation and subjecting them to the known higher morbidity rates. Depending upon the direction that future GOG cervical trials will take, it is hoped that women with stage IB tumors will not be subjected to triple modality therapy. The real study question for woman with bulky stage I tumors is not: what is the value of post-operative radiotherapy?; but, what is the value of radiotherapy compared to concurrent chemo-radiotherapy? Russell wrote an outstanding review in the same issue of Gynecologic Oncology [73: 175-176; 1999]. Also, an outstanding review is forthcoming from Koh in the upcoming January issue of Seminars in Radiation Oncology. The January issue of Seminars in Radiation Oncology is devoted exclusively to recent developments in gynecologic oncology. ****************** GI / Soft Tissue Sarcoma: Tepper 12/99 AU: Pollack A; Zagars GK; Goswitz MS; Pollock RA; Feig BW; Pisters PW. TI: Preoperative vs. postoperative radiotherapy in the treatment of soft tissue sarcomas: a matter of presentation. SO: Int J Radiat Oncol Biol Phys 1998 Oct 1;42(3):563-72. Abstract: PURPOSE: Radiotherapy for soft tissue sarcoma is typically preoperative or postoperative, with advocates of each. In this study, the relationship of the sequencing of radiotherapy and surgery to local control was examined. METHODS AND MATERIALS: The cohort consisted of 453 patients with Grade 2-3 malignant fibrous histiocytoma, synovial sarcoma, or liposarcoma treated from 1965-1992. Retroperitoneal sarcomas were excluded. Median follow-up was 97 months. There were 3 groups of patients that were classified by the treatment administered at our institution: preoperative radiotherapy to a median dose of 50 Gy given before excision at MDACC (Preop; n equals 128); postoperative radiotherapy to a median dose of 64 Gy given after excision at MDACC (Postop; n equals 165); and radiotherapy to a median dose of 65 Gy without excision at MDACC (RT Alone; n equals 160). Those in the RT Alone Group had gross total excision at an outside center prior to referral. RESULTS: Histological classification, whether locally recurrent at referral, and final MDACC margins were independent determinants of local control in Cox proportional hazards multivariate analysis using the entire cohort. The type of treatment was not significant; however, tumor status at presentation (gross disease vs. excised) affected these findings greatly. Gross disease treated with Preop was controlled locally in 88% at 10 years, as compared to 67% with Postop (p equals 0.01). This association was independently significant for patients treated primarily (not for recurrence). In contrast, for those presenting after excision elsewhere, 10-year local control was better with Postop (88% vs. 73%,p equals 0.07), particularly for patients treated primarily (91% vs. 72%, p equals 0.02 in univariate analysis; p equals 0.06 in multivariate analysis). Re-excision at MDACC (Postop) resulted in enhanced 10-year local control over that with RT Alone (88% vs. 75%, p equals 0.06), and was confirmed to be an independent predictor in multivariate analysis (p equals 0.02). CONCLUSION: Local control was highest with Preop in patients presenting primarily with gross disease, and with Postop in patients presenting primarily following gross total excision. The data suggest that 50 Gy is inadequate after gross total excision, possibly due to hypoxia in the surgical bed. Editor's comments: This article is interesting in that it raises the possibility that the prior treatment of soft tissue sarcomas may effect both outcome and the proposed treatment. It is unfortunately true that many patients with a diagnosis of STS come for their definitive therapy after a resection performed by a surgeon who did not think they were treating a sarcoma. It has been well demonstrated that after the resections performed in this clinical situation that there is a very high likelihood of gross residual disease. Therefore, many institutions recommend that re-excisions be routinely performed in this clinical situation. The question is often raised as to whether adjuvant radiation therapy should be given before or after the re-excision. Because of the opinions of many that preoperative radiation therapy is preferable to postoperative therapy when patients are seen primarily, this approach has been carried over to the postresection clinical situation, although clearly this is not true "preoperative" therapy. In this report, where the treatments were not randomized so that the possibility of bias clearly exists, there is evidence that preoperative radiation therapy is preferable if the patient is being treated initially. However, the results appeared better with postoperative therapy after a reresection if a surgical resection had been performed on the outside rather than preooperative irradiation before the reresection. This result may appear surprising, but perhaps can be explained by a poorly vascularized tumor bed resulting from the initial surgery which is then inadequately treated with the doses typically used preoperatively (in the range of 5000 cGy). When these patients are treated after reresection, higher doses of 60-66 Gy are used which may be adequate for control of poorly vascularized tissues. I do not think the data in this paper are definitive, but they suggest that these issues need to looked at other centers treating large numbers of sarcomas. ****************** CNS: Bauman 12/99 AU: Miralbell R; Mornex F; Greiner R; Bolla M; Storme G; Hulshof M; Bernier J; Denekamp J; Rojas AM; Pierart M; van Glabbeke M; Mirimanoff RO. TI: Accelerated Radiotherapy, Carbogen, and Nicotinamide in Glioblastoma Multiforme: Report of European Organization for Research and Treatment of Cancer Trial 22933. SO: J Clin Oncol 1999 Oct;17(10):3143-3149. URL: http://www.jco.org/cgi/content/full/17/10/3143 PDF: http://www.jco.org/cgi/reprint/17/10/3143 Abstract PURPOSE: A three-step phase I/II trial associating accelerated radiotherapy with carbogen (step 1, ARCO), with nicotinamide (step 2, ARN), or with both (step 3, ARCON) was conducted, the aim of which was to overcome the effects of proliferation and hypoxia as potential causes of tumor radioresistance in glioblastoma multiforme. PATIENTS AND METHODS: Radiotherapy consisted of 60 Gy delivered over 4 weeks in 1.5-Gy fractions twice daily, 5 days a week. Carbogen breathing was started 5 minutes before each fraction and continued until the end of each treatment session. Nicotinamide was given daily as a single oral dose of 85 mg/kg. RESULTS: A total of 115 patients with a median age of 55 years were registered. Of 107 eligible patients, 23 were registered in step 1, 28 in step 2, and 56 in step 3. The planned treatment was administered without any interruption in 72% of patients (86% in ARCO but 68% in ARN and ARCON). The incidence and severity of acute skin and mucous membrane toxicity were higher in patients who received nicotinamide (ie, the ARN and ARCON groups). Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients in the ARN group and 32% of patients in the ARCON group, but only in 8% of patients in the ARCO group. Eight percent of evaluated patients presented with abnormal liver test results at treatment completion. The dose of corticosteroids had to be increased in 44% of patients. Late neurologic side effects were similar in all treatment steps and were observed mostly in patients with disease progression. Median survival times for patients treated with ARCO, ARN, and ARCON were 10.1, 9.7, and 11.1 months, respectively. CONCLUSION: Feasibility of ARCO treatment was good but that of ARN and ARCON was only fair. This probably reflected the higher acute toxicity rate, particularly gastrointestinal, for patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, suggesting a higher than expected acute neurologic toxicity. Overall survival was similar in the three treatment steps and not different when compared with results of other series that used radiotherapy alone. Editor's comments: This trial attempted to compensate for 2 known problems with glioblastoma: a high proliferation rate and a potentially large hypoxic cell component. Unfortunately, but perhaps predictably, the strategy of accelerated radiotherapy with increased oxygen delivery (by carbogen: 95% 02 + 5% CO2 and nicotinamide) produced no difference in overall survival or in the radiographic response rates. While one can quibble over whether adequate drug delivery was achieved due to nicotinamide toxicity, the results are quite consistent with other trials of hypoxic cell sensitizers with or without accelerated XRT. It would seem that the problem with glioblastomas is not solely their hypoxia or high labelling indices but rather their intrinsic radioresistance. That is, the tumors are not bad because of hypoxia and high labelling indices, rather, the tumors are hypoxic and proliferating because they are bad! Until a strategy is achieved to sensitize the bulk of the glioblastoma cells, the problems of hypoxia and accelerated proliferation (which tend to be among a fraction of the tumor cells) will be overwhelmed by the uncontrolled growth of the rest of the tumor. Ultimately, we will probably need effective strategies to address hypoxia and accelerated repopulating (and invading) cells in glioblastoma, but not for now... So, how to sensitize the bulk of the cells? Novel drug delivery methods (BBB disruption, osmotic pumps, implantable polymers) and newer chemotherapy agents may play a role. Another strategy is to examine the subset of glioblastomas that DO respond to treatment. About 10-20% of glioblastomas will have a CR or substantial PR to conventional agents. What is special about this subset of patients? How do they differ from the rank and file glioblastomas? How can we make the rank and file more like the responding patients. By looking to our successes (rather than our failures) clues to new treatment strategies may be found.... ****************** Breast: Recht 12/99 AU: Paszat LF; Mackillop WJ; Groome PA; Schulze K; Holowaty E. TI: Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada. SO: Int J Radiat Oncol Biol Phys 1999 Mar 1;43(4):755-62. Abstract: PURPOSE: To compare the risk of mortality from myocardial infarction (MI) after left-sided postlumpectomy radiotherapy (RT) to the risk after right-sided postlumpectomy RT. METHODS: We conducted a population- based cohort study of cases of invasive female breast cancer in Ontario, diagnosed between January 1, 1982 and December 31, 1987 (n equals 25,570). Records of the Ontario Cancer Registry (OCR) were linked to hospital procedure and discharge abstracts and to RT records from Ontario cancer centers. A case was labelled as lumpectomy if this was the maximum breast surgery within 4 months of diagnosis. Postlumpectomy RT occurred up to 1 year postdiagnosis. Laterality was assigned from the laterality descriptor of the RT records. A case was labelled as having had a fatal MI if ICD code 410 (myocardial infarction) was recorded as the cause of death in the OCR. We used logistic regression to compare the likelihood of utilization of: 1. Dose per fraction greater than 2.00 Gy; 2. cobalt vs. linac; and 3. boost RT. We used life table analysis and the log rank test comparing the time to fatal MI from diagnosis of breast cancer between women who received left-sided postlumpectomy RT and women who received right-sided. We used Cox proportional hazards models to study the relative risk for left-sided cases overall, and stratified by age, RT characteristics, and among conditional survival cohorts. RESULTS: Postlumpectomy RT was received by 1,555 left-sided and 1,451 right-sided cases. With follow-up to December 31, 1995, 2% of women with left-sided RT had a fatal MI compared to 1% of women with right-sided RT. Comparison of the time to failure between women who had left-sided RT and women who had right- sided RT showed the left-sided RT group to be associated with a higher risk of fatal MI (p equals 0.02). Adjusting for age at diagnosis, the relative risk for fatal MI with left-sided postlumpectomy RT was 2.10 (1.11, 3.95). CONCLUSION: Among women who received postlumpectomy RT for breast cancer in Ontario between 1982-1987, left-sided postlumpectomy RT was associated with a higher risk of fatal MI compared to right-sided. AU: Hojris I; Overgaard M; Christensen JJ; Overgaard J. TI: Morbidity and mortality of ischaemic heart disease in high-risk breast- cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. SO: Lancet 1999 Oct 23;354(9188):1425-30. URL: http://www.thelancet.com/newlancet/sub/issues/vol354no9188/article1425.html Abstract: BACKGROUND: Radiotherapy in addition to systemic treatment after mastectomy prolongs survival in high-risk breast-cancer patients. However, adjuvant radiotherapy has a potential association with ischaemic heart disease. We assessed morbidity and mortality from ischaemic heart disease in patients treated with postmastectomy radiotherapy. METHODS: Between 1982 and 1990, we randomly assigned 3083 women at high risk of breast cancer, after mastectomy, adjuvant systemic treatment with (n equals 1538) or without (n equals 1545) radiotherapy. An anterior photon field was used against the periclavicular region and the axilla. The chest wall was treated through two anterior shaped electron fields, one including the internal mammary nodes. The intended dose was 48-50 Gy in 22-25 fractions, at four to five fractions per week. We obtained information on morbidity and mortality of ischaemic heart disease over a median of 10 years. Analysis was by intention to treat. FINDINGS: More women in the no-radiotherapy group than in the radiotherapy group died of breast cancer (799 [52.5%] vs 674 [44.2%]), whereas similar proportions of each group died from ischaemic heart disease (13 [0.9%] vs 12 [0.8%]). The relative hazard of morbidity from ischaemic heart disease among patients in the radiotherapy compared with the no-radiotherapy group was 0.86 (95% CI 0.6-1.3), and that for death from ischaemic heart disease was 0.84 (0.4-1.8). The hazard rate of morbidity from ischaemic heart disease in the radiotherapy group compared with the no-radiotherapy group did not increase with time from treatment. INTERPRETATION: Postmastectomy radiotherapy with this regimen does not increase the actuarial risk of ischaemic heart disease after 12 years. Editor's comments: These two important articles come to diametrically opposed conclusions as to the long-term risk of cardiac disease faced by patients undergoing radiotherapy for breast cancer. the critical factor is probably fraction size. In the Ontario study, the great majority of patients were treated with 2.5-Gy fractions; in the Danish trials, 2-Gy fractions. The significance of this finding is even more striking when one considers that there was likely a smaller volume of heart treated in patients in Ontario (where only breast tangential fields were used) than in Denmark (where the internal mammary nodes were treated with electrons). There are numerous implications of these data. One is that it will take many years to fully assess the desirability of different fractionation schemes (being tested in randomized trials in Ontario and the UK). Second, the irradiated cardiac volume may be less important in the risk of developing such long-term problems than we have thought, at least up to a certain point; but where such a threshold of risk lies is unknown. Finally, the larger fraction sizes used in Ontario are similar to those used in older trials of postmastectomy radiotherapy, which clearly was associated with an increased risk of non-breast cancer mortality in the 1995 Oxford overview (see N Engl J Med 1995;333:1444-55). The findings in the Danish trials are more likely to be representative of results with modern radiotherapy techniques using 1.8-2 Gy fractions. Hence, the net long-term benefits of postmastectomy radiotherapy are likely to be greater than those found in the Overview. However, while the Danish results are reassuring, it is important to note that none of the patients in their trials received anthracyclines, taxanes, Herceptin, or any of the potentially cardiotoxic systemic agents coming into widespread use in both node-negative and node-positive patients. Hence, the debate over optimal treatment volumes (particularly with regards to deliberate inclusion of the internal mammary nodes) and techniques remains relevant. ****************** RES: Hoppe 12/99 AU: Wasserman TH, Petroni GR, Millard FE, Chung CT, Barcos M, Johnson JL, Canellos GP, Peterson BA. TI: Sequential chemotherapy (etoposide, vinblastine, and doxorubicin) and subtotal lymph node radiation for patients with localized Hodgkin disease and unfavorable prognostic features: A phase II Cancer and Leukemia Group B Study (9051). SO: Cancer 1999 Oct 15;86(8):1590-5. Abstract: BACKGROUND: The aim of this study was to evaluate a regimen of sequential chemotherapy and radiotherapy for patients with Hodgkin disease. METHODS: The Cancer and Leukemia Group B conducted a Phase II study of three cycles of etoposide, vinblastine, and doxorubicin (EVA) chemotherapy followed by subtotal lymph node radiation for patients with localized Hodgkin disease and unfavorable prognostic features. Fifty-nine patients were enrolled in the study. Fifty-three patients met all study eligibility criteria; 48 of them (91%) had mediastinal disease and 29 (55%) had bulky mediastinal disease. RESULTS: A complete response (CR) occurred in 35 of the patients (66%). Of all patients who had CR, 26% had the CR after the chemotherapy and before the radiation, and 74% after the chemotherapy and radiation. Twenty percent of the patients who had CR experienced disease progression; in these patients, the progression was outside the radiotherapy field in the lung and involved widespread disease. CONCLUSIONS: EVA offers a nonbleomycin-containing alternative for patients in whom preexisting pulmonary disease may be exacerbated by bleomycin and radiation therapy. EVA, as given in this study (in three cycles), was insufficient chemotherapy for patients who had disease in areas outside the radiation fields (occult disease). Copyright 1999 American Cancer Society. Editor's comments: At a time when the trend has been to decrease the aggressiveness of therapy in order to decrease potential long term toxicity for patients with Hodgkin's disease, this CALGB study provides a reminder that we can go too far. In this Phase 2 trial, patients with early stage HD and unfavorable characteristics (Bulky mediastinal disease [55% of patients] or a combination of other relatively unfavorable factors) were treated with a modified chemotherapy program that included 3 cycles of EVA (etoposide, vinblastine, and doxorubicin) followed by STLI (39.6 Gy to mantle, 30.6 Gy to PA/spleen). The CR rate was only 66%, and 20% of the complete responders experienced treatment failure in a relatively short time. The observation that most of the failures were outside the primary radiation field (especially pulmonary parenchyma) emphasizes the established fact that the lungs are at risk as a site of failure in the presence of a large mediastinal mass and also demonstrates that 3 cycles of EVA is inadequate to ablate occult Hodgkin's disease. This study also reinforces the observation of the EORTC H7U randomized trial in which patients with stage I-II HD and unfavorable disease characteristics were randomized to 6EBVP II + IF RT vs. 6MOPP/ABV + IF RT. Event-free survival was only 68% in the EBVP arm vs. 90% in the MOPP/ABV arm (p less than .0001), despite the fact that the EBVP + RT combination was adequate in the H7F patients with early stage disease and favorable characteristics (event-free survival 90%). ****************** Lung/Mediastinum: Turrisi 12/99 AU: Bonner JA; Sloan JA; Shanahan TG; Brooks BJ; Marks RS; Krook JE; Gerstner JB; Maksymiuk A; Levitt R; Mailliard JA; Tazelaar HD; Hillman S; Jett JR. TI: Phase III Comparison of Twice-Daily Split-Course Irradiation Versus Once-Daily Irradiation for Patients With Limited Stage Small-Cell Lung Carcinoma. SO: J Clin Oncol 1999 Sep;17(9):2681. URL: http://www.jco.org/cgi/content/full/17/9/2681 PDF: http://www.jco.org/cgi/reprint/17/9/2681 Abstract: PURPOSE: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial. PATIENTS AND METHODS: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response. RESULTS: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (greater than or equal to grade 3) than those who received ODTI (12.3% v 5.3%; P equals .05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation. CONCLUSION: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI. Editor's comments: This is an interesting trial that used slightly higher doses: 48 Gy in BID versus 50.4 in QD fractionation. When the Mayo first piloted this regimen, it showed slightly less local control than the Penn trial, who's dose and fractionation scheme was used in the Intergroup study. My unsolicited (and unheeded) advice was that the split course was a mistake. Spilt course defeats the purpose of BID -- rapidly proliferating cells need to be treated more frequently than with a 24 hour interval. In the early 70's or 60's, split course was standard -- to allow for re-oxygenation; repair; and re-distribution -- the re-population was to occur in the normal tissue, but perhaps with magic, not in the tumor. We now know that this is true in head and neck cancers, and this study suggests that it is true in small cell lung cancer. The other factor in this study is the delay to cycle number four for concurrent therapy. While this continues to be the subject of some confusion and debate, in the platinum-etoposide era early concurrent therapy has always been better than delaying thoracic radiotherapy. In the studies that assert the contrary, the timing variable has not been cleanly isolated. The classic CALGB study by Perry not only delayed radiotherapy, but the chemotherapy doses were remarkably attenuated in the early thoracic radiotherapy trial. The Aarhus trial used pre or post chemotherapy radiation treatment, not early or delayed concurrent therapy -- again also using split course, the local failure rate was greater than 75% whether the thoracic radiotherapy was given before or after the 9 cycles of chemotherapy. (The Etoposide was also given in a single dose and in only 3 cycles of the 9 employed). The Goto report in this year's ASCO and Jeremic have provided strong evidence that delays in the concurrent use of chemotherapy are bad. We can add the Mayo report to the list of trials that prove that split course and delayed concurrent therapy produce inferior results. Why did they do this? They wanted to reduce esophagitis. They did. There was less esophagitis on the Mayo BID than the intergroup QD treatment. There has been a Q-Twist analysis that infers that the patients do not remember their esophagitis -- it is transient, it goes away in some cases in as long as three months. Rarely there is a transient stricture, but these can be dilated once or twice without permanent strictures. My read is the reduction of esophagitis as demonstrated in the Mayo report is at the price of poorer survival. Perhaps other strategies are warranted (field reductions, ethyol) but split course is an unattractive, potentially dangerous option that should not be done. This paper reports a well conducted trial but with these two influential flaws that reduce the impact of twice-daily therapy. Happy holidays to all. ****************** GU: Roach 12/99 AU: Vicini FA; Kestin LL; Martinez AA. TI: The importance of adequate follow-up in defining treatment success after external beam irradiation for prostate cancer. SO: Int J Radiat Oncol Biol Phys 1999 Oct 1;45(3):553-61. Abstract: PURPOSE: We reviewed our institution's experience treating patients with localized prostate cancer with external beam radiation therapy (RT) to determine how differences in the length of follow-up affect the determination of treatment outcome using the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel Definition of biochemical failure (BF). METHODS AND MATERIALS: From January 1987 through December 1997, 1109 patients with localized prostate cancer were treated with definitive external beam RT at William Beaumont Hospital, Royal Oak, Michigan. All patients received external beam RT to a median total prostate dose of 66.6 Gy (range: 59.4-70.4 Gy). A total of 1096 patients (99%) had sufficient prostate-specific antigen (PSA) follow-up to determine their biochemical status. To test the impact of differences in follow-up on the calculation of BF, 389 patients with at least 5 years of PSA follow-up were selected as the reference group for the initial analysis. BF was then retrospectively determined using the Consensus Panel definition at yearly intervals, ignoring the remainder of each patient's follow-up. The median follow- up for this group of patients was 6.6 years (range: 5.0-11.6 years). In a second analysis, patient cohorts were randomly selected with varying median PSA follow-up intervals in order to more accurately represent a population whose follow-up is distributed continuously over a defined range. Seven cohorts were randomly selected with 200 patients in each cohort. Cohorts were individually identified such that half of the patients (100) had 2 years or less follow-up than the stated time point for analysis and half (100) had up to 2 years more follow-up than the time point chosen for analysis. For example, in the cohort with a median follow-up of 3 years, 100 patients with a PSA follow-up from 1 to 3 years were randomly selected, and 100 patients with a follow-up from 3 to 5 years were randomly selected, thus generating a median follow-up of 3 years for this cohort (range: 1 to 5 years). This process was repeated five times for five random samples of seven cohorts each. Biochemical failure was calculated according to the Consensus Panel definition. RESULTS: In the first analysis, significantly different rates of biochemical control (varying by 6-21%) were calculated for the same actuarial year chosen for analysis depending only upon the length of follow-up used. For example, the 3-year actuarial rate of biochemical control (BC) varied from 71% when calculated with 3 years of follow-up versus 50.4% with 7 years (p less than 0.01). These differences in actuarial rates of BC were observed in all subsets of patients analyzed (e.g., PSA less than 10, Gleason less than or equal to 6, n eqauls 132,p less than 0.001; PSA less than 10, Gleason greater than or equal to 7, n equals 33, p equals 0.03; PSA greater than or equal to 10, Gleason less than or equal to 6, n equals 109, p less than 0.001; and PSA greater than or equal to 10, Gleason greater than or equal to 7, n equals 72, p equals 0.002). The absolute magnitude of the difference in actuarial rates of BC was greatest during years 2 (range 18-30%), 3 (range 16-25%), and 4 (range 15-24%) after treatment. In the second analysis using median PSA follow-ups (as defined above), statistically significant differences in actuarial rates of BC were again observed. For example, the 3-year actuarial rate of BC varied from 74.8% with a median follow-up of 2 years versus 49.2% with a median follow-up of 6 years. These dramatic differences in BC were still observed beyond 5 years. CONCLUSION: When the ASTRO Consensus Panel definition of BF is used to calculate treatment success with external beam RT for prostate cancer, adequate follow-up is critical. Depending upon the length of time after treatment, significantly different rates of BC (varying by 15% to 30%) can be calculated for the same time interval chosen for analysis. These results suggest that data should only be reported if the length of follow-up extends at least beyond the time point at which actuarial results are examined for the majority of patients. Editor's comments: The recent report by Vicini et al. deserves special attention. These authors show how differences in follow-up can impact on the conclusions of the analysis. There are a number of implications that result from this report: First, numerous retrospective studies that show that some "new" treatment is better could simply reflect differences in the duration of follow-up. Secondly, if the authors are correct, a median follow-up of 2 years beyond the time point chosen (e.g. 4 years) would be required to be accurate! This second conclusion must be viewed with great caution! The authors created a false senario with artifically "tight" follow-up intervals. For example, they created groups of patients with a median follow-up of 3 years +/- 2 years (1 - 5 years). However, the authors ignore the fact that the ASTRO consesus definition requires a minimum follow-up of 2 years. They also fail to consider what happens if a group of patients have a median follow-up of 3 years but a range of 2 to 7 years. In figure 1 they show a group of curves that appear to be flat and inaccurate. How would these curves look if the minimum follow-up was 2 years and a wider range was used? They must be commended for this thought provoking paper. It brings to mind the old saying "It ain't over til it's over". ****************** Radiobiology: Withers 12/99 No Reference Selected ****************** Health Services Research: Hayman 12/99 AU: Ng AK; Weeks JC; Mauch PM; Kuntz KM. TI: Decision Analysis on Alternative Treatment Strategies for Favorable- Prognosis, Early-Stage Hodgkin's Disease. SO: J Clin Oncol 1999 Nov;17(11):3577-3585. URL: http://www.jco.org/cgi/content/full/17/11/3577 PDF: http://www.jco.org/cgi/reprint/17/11/3577 Abstract: PURPOSE: To compare the therapeutic outcomes of various treatment strategies in early-stage, favorable-prognosis Hodgkin's disease (HD) using methods of decision analysis. METHODS: We constructed a decision-analytic model to determine the life expectancy and quality-adjusted life expectancy for a hypothetical cohort of clinically or pathologically staged 25-year-old patients with early-stage, favorable- prognosis HD treated with varying degrees of initial therapy. Markov models were used to simulate the lifetime clinical course of patients, and baseline probability estimates were derived from published study results. RESULTS: Among patients with pathologic stage (PS) I to II, mantle and para-aortic (MPA) radiotherapy was favored over combined- modality therapy (CMT), mantle radiotherapy, and chemotherapy by 1.18, 1.33, and 1.55 years, respectively. For patients with clinical stage (CS) I to II, the treatment options of MPA-splenic radiotherapy, CMT, and chemotherapy yielded similar survival outcomes. Sensitivity analysis showed that the decision between CMT and MPA-splenic radiotherapy was highly influenced by the precise values of the estimates of treatment efficacy and long-term morbidity, the quality-of- life value assigned to the postsplenic irradiation state, and the time discount value used in the model. Probabilistic sensitivity analysis demonstrated that even if future studies doubled the precision of the estimates of the treatment-related variables, it would be impossible to demonstrate the superiority of one treatment over the other. CONCLUSION: Our model predicted that on average, MPA radiotherapy was clearly the preferred treatment for PS I to II patients. For CS I to II patients the treatment decision is a toss-up between MPA-splenic radiotherapy and CMT, emphasizing the importance of patient preference exploration and shared decision making between patient and physician when choosing between treatments. Editor's comments: This decision analysis addresses a hotly debated and controversial topic in the radiation oncology community: what is the "optimal" treatment strategy for patients with clinical stage (CS) I-IIA and pathologic stage (PS) I-IIA Hodgkin's disease (HD)? To date, most of the randomized clinical trials that have been performed in early-stage HD have only compared two strategies and have not evaluated these strategies based on potential differences in quality of life (QOL). In addition, the length of follow-up of these trials is relatively short, especially given the fact that most patients with early-stage HD are young and will be cured and, therefore, will be at risk of developing late life-threatening treatment-related toxcities for many years. Decision analyses are often useful in clinical situations in which the available outcomes data are limited in terms of either the types of treatment strategies compared and/or the length of follow-up. In addition, these analyses can also allow for the incorporation of QOL into the assessment of the incremental benefit of competing interventions. Accordingly, the management decisions regarding the treatment of patients with good-prognosis, early-stage HD are ideally suited to be evaluated through the use of Markov models, a decision analysis technique. In their analysis, Ng and colleagues were able to draw on the extensive "traditional" outcomes data (i.e., survival, relapse and complication rates) which are available for the competing strategies for PS and CS patients. Although they should be commended for trying to incorporate quality of life into their analysis through the use of utilities and quality adjusted life years (QALYs), unfortunately, primary utility data do not exist for the relevant health states and, therefore, the authors were forced to rely on "expert opinion" (which, while a potential limitation of their analysis, is not at all uncommon in decision analyses). Based on currently available clinical data, MPA appeared to be the treatment of choice for PS patients while, for CS patients, the choice between MPA and CMT was less clear. As part of their sensitivity analysis, it should also be noted that the authors included a so-called probabilistic analysis (also known as a Monte Carlo simulation). When doing such an analysis, the values of selected key variables in the model are drawn at random from their probability distributions and, therefore, rather than generating just a point estimate, one can generate confidence intervals or estimate the probability that one strategy will be preferred over the other. Hopefully this decision analysis will help clinicians to consolidate and clarify what sometimes seems, at least to me, to be the morass of clinical data on this subject. It will be interesting to see how this issue plays out in the future as more clinical and quality of life data become available. ****************** Best Wishes for the Holiday Season! Brian J. Goldsmith, M.D. Moderator, IROJC