From owner-radoncjc@net.bio.net Mon Mar 6 09:12:00 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 85A0E17A81; Mon, 6 Mar 2000 09:11:55 +0000 (GMT) Received: from iron.hgmp.mrc.ac.uk (iron [193.62.192.26]) by hgmp.mrc.ac.uk (8.9.3/8.9.3) with ESMTP id JAA26540 for ; Mon, 6 Mar 2000 09:11:52 GMT Received: (from mfaller@localhost) by iron.hgmp.mrc.ac.uk (8.9.3+Sun/8.8.8) id JAA21862 for radoncjc-list; Mon, 6 Mar 2000 09:11:52 GMT Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id 277B717ABC; Fri, 3 Mar 2000 21:42:14 +0000 (GMT) To: radoncjc@hgmp.mrc.ac.uk Subject: March 2000 Internet Radiation Oncology Journal Club (IROJC) Reply-To: radoncjc@hgmp.mrc.ac.uk Date: ri, 03 Mar 2000 16:37:23 -0500 From: Brian Goldsmith Message-Id: <20000303214214.277B717ABC@mercury.hgmp.mrc.ac.uk> Sender: owner-radoncjc@net.bio.net Precedence: bulk March 2000 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 58th 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. 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. ------------------------------------------------------------ ARCHIVED IROJC material is available at http://www.bio.net/hypermail/radoncjc/ ------------------------------------------------------------ Commentary Rules: (1) Please cite the subject category in the header of your e-mail message, e.g., Subject: CNS 3/00. (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 3/00 AU: Hovi L; Saarinen-Pihkala UM; Vettenranta K; Lipsanen M; Tapanainen P. TI: Growth in children with poor-risk neuroblastoma after regimens with or without total body irradiation in preparation for autologous bone marrow transplantation. SO: Bone Marrow Transplant 1999 Nov;24(10):1131-6. Abstract: Impaired growth after TBI prior to BMT has been a constant finding in children with leukemia. The growth of poor-risk neuroblastoma (NBL) survivors treated with myeloablative preparative regimens and ABMT at the Hospital for Children and Adolescents, University of Helsinki, since 1982 is reported. Two separate groups were analyzed: (1) The TBI- patients (n = 15) were conditioned with high-dose chemotherapy only. They had been treated at the age of 1.0-6.3 (mean 3.0) years and the post-ABMT follow-up time was 1.5-14.5 (mean 7.7) years. (2) The TBI+ patients (n = 16) had received TBI in addition to high-dose chemotherapy. They had been treated at the age of 1.3-4. 8 (mean 3.0) years, and the post-ABMT follow-up time was 1.5-8.0 (mean 4.7) years. The height standard deviation score (SDS) was similar for the two groups at the time of diagnosis, -0.3 +/- 1.2 (mean +/- s.d.), and at the time of ABMT, -0.7 +/- 1.1. After transplantation, the height SDS continued to decrease in the TBI+ group, the mean being -2.0 SDS at 5 years after ABMT. In the TBI-group, the mean height SDS remained within -0.7 to -0.9 to the 10 years of follow-up. Five patients received growth hormone (GH) therapy starting 2-6 years after ABMT. They all had low GH secretion in provocative tests. All showed some response to GH therapy. The mean height SDS increased 0.4 SDS during the 3 years following the start of GH therapy, while in the untreated patients a decrease of 0. 8 SDS during the corresponding time (P = 0.009) was observed. We conclude that NBL patients grow poorly following ABMT when TBI is included in the conditioning regimen, but close to normally when treated without TBI. The need for GH therapy should be evaluated early to avoid an unnecessary decrease in final height. Editor's comments: There is considerable enthusiasm in the Pediatric Oncology community about the use of intensive chemotherapy, total-body irradiation and autologous bone marrow transplantation for children with high-risk (poor-risk) neuroblastoma. This enthusiasm has mounted since Matthay et al reported their results of chemotherapy, TBI, and ABMT with 13-Cis-Retinoic Acid for high-risk neuroblastoma in The New England Journal of Medicine 34:1165-1173, October 14, 1999. This randomized study did show superior results with ABMT including TBI as compared to chemotherapy alone. However, studies of toxicity have not been well studied. The article by Hovi et al from Finland discusses the growth alterations following ABMT with TBI as compared to regimens that do not use TBI, and show a significant imparement in growth among the TBI treated cohort. They conclude that such children should be evaluated for growth hormone replacement. Children with high risk neuroblastoma continue to fair poorly. Perhaps ABMT with TBI will improve outcome, but the stakes are high, and toxicity is high. We have not yet hit a "home run" in our management approaches for children with high risk neuroblastoma. ****************** Head/Neck/Skin: Foote 3/00 AU: Lacy PD; Piccirillo JF; Merritt MG; Zequeira MR. TI: Head and neck squamous cell carcinoma: better to be young. SO: Otolaryngol Head Neck Surg 2000 Feb;122(2):253-8. URL: http://www1.mosby.com/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artType=full&id=a99281 Abstract: Most head and neck squamous cell carcinoma patients are elderly, with few younger than 40 years. Controversy exists in the literature regarding outcomes for younger patients. The goal of this research project was to compare baseline features and outcomes for young patients (/=65 years). To investigate the relationship between age and important presenting features and outcomes, 1160 recently diagnosed patients first treated at Washington University between 1980 and 1991 were identified from an existing database. Full 5-year survival information was available for 1030 patients (89%). Overall, the 5-year survival rate was 46% (478/1030); young patients (65%, 26/40) had a significantly better survival rate than middle-aged (52%, 292/566) or old patients (38%, 160/424) (chi(2) = 24.5; P = 0. 001). Survival was also related to smoking, comorbidity, primary site, TNM stage, and nodal disease. Age remained a significant factor even after we controlled for these other factors. Young patients developed fewer recurrent and new primary tumors. We conclude that young patients have a much better overall prognosis than older patients. The reasons for this difference are unclear, but it appears that the impact of age goes beyond an actuarial effect. ****************** GYN: Petereit 3/00 AU: Petereit DG, Tannehill SP, Grosen EA, Hartenbach EM, Schink JC. TI: Outpatient vaginal cuff brachtherapy for endometrial cancer. SO: Int J Gynecol Cancer 1999, 9, 456-462. Abstract: The objective of this study was to determine the efficacy and complications of postoperative high-dose-rate (HDR) vaginal-cuff brachytherapy (VCB) in patients with endometrial carcinoma. Between August 1989 to September 1997, 191 patients were treated postoperatively after a total abdominal hysterectomy and bilateral salpingo-oopherectomy (TAH/BSO) with outpatient adjuvant HDR VCB for low-risk endometrial cancer (IB - 84%, grade 1 or 2 - 96%). Patients were treated with 2 HDR fractions, delivered one week apart while under conscious sedation (16.2 Gy x 2 to the vaginal surface). All clinical endpoints were calculated using the Kaplan Meier method. The median time in the brachytherapy suite was 60 minutes in which no acute complications were observed. The 30-day morbidity and mortality rates were both 0%. With a median follow-up of 38 months (12-82 months), the 4-year survival, relapse-free survival, and vaginal control rates were 95%, 98%, and 100%, respectively. One patient developed a colo-vaginal fistula at 5 years. Adjuvant HDR VCB in 2 outpatient insertions produced 100% vaginal control rates with minimal morbidity. The advantages of high dose-rate compared to low dose-rate vaginal brachytherapy include patient convenience, markedly shorter treatment times (1 h per insertion), and reduction in the cost and potential morbidity of hospitalization. HDR brachytherapy approach is a cost-effective alternative to either low-dose-rate brachytherapy or whole pelvic radiotherapy in carefully selected patients. Editor's comments: The optimal management of women with low- to intermediate-risk endometrial cancer is unclear. In November I reviewed the Mohan et al paper which suggested that aggressive surgical staging improved survival (1). In January I reviewed the Nauman et al. paper which assessed the attitudes of gynecologic oncologists in treating stage I endometrial cancer - especially in light of GOG #99 [randomized trial of pelvic radiotherapy versus observation after surgery] (2). We just published our experience in treating women with stage I endometrial cancer from the University of Wisconsin using HDR vaginal cuff brachytherapy alone after surgery. The Wisconsin study had similar percentages of low-risk patients (96% grade 1 and 2, 84% stage IB) when compared to GOG #99 (80% grade 1 and 2, 60% stage IB) and the Mohan study (94% grade 1 and 2, 83% stage IA/IB). With two fractions separated by one week, our 4-year vaginal control rates were 100% with only 1 of 191 patients suffering a significant complication - single colo-vaginal fistula. 16.2 Gy X 2 was delivered at the surface using ovoids delivering a 60 Gy LDR equivalent at 100 rads/h. Only one patient suffered a pelvic nodal failure. Although this fractionation schedule sounds rather "hot", it actually delivers a lower dose to the vaginal surface than a more commonly used HDR fractionation schedule of 7 Gy X 3 @ 5 mm. Nearly two-thirds of patients in this analyis had minimal to no lymph nodes sampled. The 4-year disease-free survival of 98% was higher than that observed in GOG #99 and the Mohan study: both latter studies had selective to complete lymphadenectomies. While the Wisconsin Experience may not be comparable to the other studies, it does provide additional data questioning the need to pursue aggressive lymph node dissections for low-risk endometrial patients: grade 1 and 2/stage IA and IB. The morbidity of treating endometrial patients tends to be underemphasized. In the GOG #99 trial, a non-actuarial grade 3 bowel complication rate OF 8% was observed when pelvic radiotherapy was given after a lymphadenectomy. In the Mohan trial, surgical staging alone was associated with a 13% (non-actuarial) significant morbidity rate. The dilemma in managing these highly curable patients is a balance between selectively offering effective adjuvant therapy, and not overtreating - whether with surgical staging or pelvic radiotherapy. 1. Mohan DS, Samuels MA, Selim MA, et al. Long-term outcomes of therapeutic pelvic lymphadenectomy for stage I endometrial adenocarcinoma. Gynecologic Oncology 1998;70:165-171. 2. Naumann RW, et al. The use of adjuvant radiation therapy by members of the Society of Gynecologic Oncologists. Gynecologic Oncology 1999;75:4-9. ****************** GI / Soft Tissue Sarcoma: Tepper 3/00 AU: Steele GD Jr, Herndon JE, Bleday R, Russell A, Benson A 3rd, Hussain M, Burgess A, Tepper JE, Mayer RJ. TI: Sphincter-sparing treatment for distal rectal adenocarcinoma. SO: Ann Surg Oncol 1999 Jul-Aug;6(5):433-41. Abstract: BACKGROUND: Studies suggest that the anal sphincter can be preserved in some patients with distal rectal adenocarcinoma (DRA), but this has not been validated in any prospective multi-institutional trial. METHODS: To test the hypothesis that the anal sphincter can be preserved in some patients with DRA, the Cancer and Leukemia Group B and collaborators reviewed 177 patients who had T1/T2 adenocarcinomas < or = 4 cm in diameter, which encompassed < or = 40% of bowel wall circumference, and were < or = 10 cm from the dentate line. Of the 177 patients, 59 patients who were eligible for the study had T1 adenocarcinomas and received no further treatment; 51 eligible T2 patients received external beam irradiation (5400 cGy/30 fractions 5 days/week) and 5-fluorouracil (500 mg/m2 IV d1-3, d29-31) after local excision. RESULTS: At 48 months median follow-up, 6-year survival and failure- free survival rates of the eligible patients are 85% and 78% respectively. Three patients died of unrelated disease. Two patients were treated for second primary colorectal tumors; both remain disease free (NED). Another eight patients died of disease, four with distant recurrence only. One T1 patient is alive with distant disease. Two T1 and seven T2 patients experienced isolated local recurrences; all underwent salvage abdominoperineal resection (APR). After APR, one T1 and four of seven T2 patients were NED at the time of last visit (2-7 years). One T1 patient died of local and distant disease. Three of seven T2 patients died with distant disease. CONCLUSIONS: We conclude that sphincter preservation can be achieved with excellent cancer control without initial sacrifice of anal function in most patients. After local recurrence, salvage resection appears effective, but longer follow-up time of local and distant disease-free survival is advised before extrapolation to patients with T3 primaries. AND AU: Chakravarti A, Compton CC, Shellito PC, Wood WC, Landry J, Machuta SR, Kaufman D, Ancukiewicz M, Willett CG. TI: Long-term follow-up of patients with rectal cancer managed by local excision with and without adjuvant irradiation. SO: Ann Surg 1999 Jul;230(1):49-54. Abstract: OBJECTIVE: The long-term outcomes of patients undergoing local excision with or without pelvic irradiation were examined to define the role of adjuvant irradiation after local excision of T1 and T2 rectal cancers. METHODS: Ninety-nine patients with T1 or T2 rectal cancers underwent local excision with or without adjuvant irradiation at Massachusetts General Hospital and Emory University Hospital between January 1966 and January 1997. Of these, 52 patients were treated by local excision alone and 47 patients by local excision plus adjuvant irradiation. Twenty-six of these 47 patients were treated by irradiation in combination with 5-fluorouracil chemotherapy. The outcomes of these groups were compared. RESULTS: The 5-year actuarial local control and recurrence-free survival rates were 72% and 66%, respectively, for the local excision alone group and 90% and 74%, respectively, for the adjuvant irradiation group. This improvement in outcome was evident despite the presence of a higher-risk patient population in the adjuvant irradiation group. Adverse pathologic features such as poorly differentiated histology and lymphatic or blood vessel invasion decreased local control and recurrence-free survival rates in the local excision only group. Adjuvant irradiation significantly improved 5-year outcomes in patients with high-risk pathologic features. Four cases of late local recurrence were seen at 64, 72, 86, and 91 months in the adjuvant irradiation group. CONCLUSIONS: The authors recommend adjuvant chemoradiation for all patients undergoing local excision for T2 tumors, and for T1 tumors with high-risk pathologic features. The four cases of late local failures beyond 5 years in the adjuvant irradiation group underscores the need for careful long-term follow-up in these patients. Editor's comments: These papers are important as they both stress the uncertainties in the management of localized rectal cancer with minimal surgical procedures with or without adjuvant irradiation. The Chakravarti paper is based on the experience from two institutions while the Steele paper is the initial results of the CALGB/Intergroup study. Management was similar in both studies. The CALGB/Intergroup study treated all T-1 tumors with local excision alone and the the T-2 with postoperative RT + bolus 5-FU. This was generally done in the Chakravarti report although it was not consistent since the paper was retrospective. In both studies the outcome was not as good as was expected when these studies were begun. There had been a strong feeling that this combination would produce very high local controls in these patients with early stage disease. The Chakravarti paper strongly suggests that radiation was beneficial in decreasing recurrence rates. However, even with RT the 5-year recurrence free survival was only 74% in these patients with early disease. Of great concern is the fact that there were 4 patients with late recurrence in the adjuvant radiation group, as long as 7 1/2 years after treatment. The Intergroup study did a little better with a 78% 6-year failure free survival. In addition, many of the local failures so far appeared to be salvaged effectively with an APR, although longer follow-up will be necessary to confirm this finding. I think that the conclusion from these studies is that local excision +/- postoperative radiation therapy and 5-FU can be used effectively in treating very selected patients with adenocarcinomas of the distal rectum. However, selection is critical to avoid high local failure rates and late failures can occur. In addition, we need to carefully present to our patients the fact that there likely is a higher risk of local failure and perhaps distant metastases with this more conservative approach, although the magnitude of the difference is unknown. ****************** CNS: Bauman 3/00 AU: Timmermann B, Kortmann RD, Kuhl J, Meisner C, Slavc I, Pietsch T, Bamberg M. TI: Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the German prospective trials HIT 88/89 and HIT 91. SO: Int J Radiat Oncol Biol Phys 2000 Jan 15;46(2):287-95. Abstract: PURPOSE: To evaluate the outcome in children with anaplastic ependymomas after surgery, irradiation, and chemotherapy; and to identify prognostic factors for survival. METHODS AND MATERIALS: Fifty-five children (n = 27 girls, 28 boys; median age at diagnosis, 6.2 years) with newly diagnosed anaplastic ependymomas were treated in the multicenter, prospective trials HIT 88/89 and HIT 91. Macroscopic complete resection was achieved in 28 patients; 27 patients underwent incomplete resection. All patients received chemotherapy before (n = 40) or after irradiation (n = 15). The irradiation volume encompassed either the neuraxis followed by a boost to the primary tumor site (n = 40) or the tumor region only (n = 13). No radiotherapy was administered in two patients. RESULTS: Median follow-up was 38 months. The overall survival rate at 3 years after surgery was 75.6%. Disease progression occurred in 25 children with local progression occurring in 20. The median time to disease progression was 45 months. The only significant prognostic factor was the extent of resection (estimated progression-free survival [EPFS] after 3 years was 83.3% after complete resection and 38.5% after incomplete resection) and the presence of metastases at the time of diagnosis (0% vs. 65.8% 3-year EPFS in localized tumors). Age, sex, tumor site, mode of chemotherapy, and irradiation volume did not influence survival. CONCLUSIONS: Treatment centers should be meticulous about surgery and diagnostic workup. Because the primary tumor region is the predominant site of failure it is important to intensify local treatment. Dose escalation by hyperfractionation or stereotactic radiotherapy might be a promising approach in macroscopically residual disease. The role of adjuvant chemotherapy requires further study. Editor's comments: This manuscript reports on a subset of patients with anaplastic ependymoma treated on a prospective trial for pediatric patients with malignant brain tumors. The 55 patients describe were reasonably uniformly staged, treated and followed and represent one of the larger series of patients treated for anaplastic ependymoma. It is worth noting that of over 600 patients enrolled on the trial over 73 institutions, only 55 met the criteria of anaplastic ependymoma, highlighting the relative infrequency of this tumor. All patients had maximal surgical resection and adjuvant radiation and chemotherapy. Radiation was localized for supratentorial tumors and craniospinal for infratentorial tumors, those with documented CSF spread and those with supraventricular tumors with ventricular infiltration. While the authors state the patients had MRI and CSF evaluation of the craniospinal axis, in fact, only 20 had CSF done, 35 had MRI. Thus, the group may have been understaged with respect to the craniospinal axis. As in other series, those children with a macroscopically complete resection did better than those with subtotal resection, and those with localized tumors did better than those with disseminated tumors. Patterns of failure were predominantly local with only 5% of children failing in the CSF exclusively. There were no differences in survival among those children with supratentorial tumors whether or not they received craniospinal radiation vs local field irradiation. The authors stated that "chemotherapy did not alter the prognosis" but didn't present comparisons between the 2 chemotherapy regimes used: adjuvant vs. neoadjuvant. This series highlights the importance of local control for children with ependymoma. Aggressive surgical resection (and perhaps in the future, focal dose escalation thru conformal techniques) to obtain local control was associated with markedly improved survival. The use of craniospinal irradiation did not seem of benefit for those patients with supratentorial tumors, even for those deemed at higher risk of CSF spread: i.e. documented ventricular infiltration. The study sheds no further light on the role of craniospinal radiation for infratentorial tumors as all patients received craniospinal radiation if they had an infratentorial site. Within the Jan 15 IJROBP there is a companion paper from the same group on medulloblastoma patients treated on the same prospective protocol as well as an editorial by Larry Kun. Also a paper on conformal radiation of the posterior fossa with an editorial by Tarbell and Loeffler. All in all, some good CNS material in this issue. ****************** Breast: Recht 3/00 AU: Cote RJ, Peterson HF, Chaiwun B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Gusterson B, Neville AM. TI: Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. International Breast Cancer Study Group. SO: Lancet 1999 Sep 11;354(9182):896-900 URL: http://www.thelancet.com/newlancet/sub/issues/vol354no9182/article896.html Abstract: BACKGROUND: This study was designed to ascertain whether immunohistochemical methods could improve the detection of metastases in primary breast-cancer patients whose axillary lymph nodes were classified, by conventional methods, as disease free. METHODS: Ipsilateral lymph nodes (negative for metastases by routine histology) from 736 patients (participants in Trial V of the International [Ludwig] Breast Cancer Study) were examined by serial sectioning and staining with haematoxylin and eosin (two sections from each of six levels) and by immunohistochemistry of a single section (with two anticytokeratins AE-1 and CAM 5.2). After median follow-up of 12 years, disease-free and overall survival were estimated by Kaplan-Meier methods. FINDINGS: Occult nodal metastases were detected by serial sectioning and haematoxylin and eosin in 52 (7%) of 736 patients and by immunohistochemistry in 148 (20%). Only two (3%) of 64 invasive lobular or mixed invasive lobular and ductal cancers had node micrometastases, detected by haematoxylin and eosin, compared with 25 (39%) by immunohistochemistry. Occult metastases, detected by either method, were associated with significantly poor disease-free and overall survival in postmenopausal but not in premenopausal patients. Immunohistochemically detected occult lymph-node metastases remained an independent and highly significant predictor of recurrence even after control for tumour grade, tumour size, oestrogen-receptor status, vascular invasion, and treatment assignment (hazard ratio 1.79 [95% CI 1.17-2.74], p=0.007). INTERPRETATION: The immunohistochemical examination of ipsilateral axillary lymph nodes is a reliable, prognostically valuable, and simple method for the detection of occult nodal metastases. Immunohistochemistry is recommended as a standard method of node examination in postmenopausal patients. Editor's comments: This is an update of the previous experience of this group on this subject. It is particularly important because of the large number of patients involved, their long follow-up time, and the careful analysis with regards to both clinical and pathologic variables (including lymphovascular invasion). However, the clinical implications of this study are not entirely clear. First, the presence of occult nodal metastases was an independent risk factor for recurrence only for postmenopausal patients. For premenopausal patients, not even a trend in this direction was seen. Finding discrepencies of this sort between subgroups tends to lessen the overall degree of confidence in the validity of such findings, of course. Second, the "true node-negative" patients in this study have poor prognoses. Although the finding of occult nodal involvement worsened that prognosis still further, it seems that both patient groups would benefit from adjuvant systemic therapy. It is not clear that the presence or absence of occult nodal involvement could be used to better tailor such treatment to the individual patient, and hence such information may be of no value once the decision to give systemic therapy has been made. Therefore, I am as yet unconvinced that immunohistochemistry should be routinely performed for patients undergoing conventional axillary dissection. (It's role in patients treated with sentinal node biopsy is also unclear; the American College of Surgeons Z010 study will hopefully answer this question.) ****************** RES: Hoppe 3/00 AU: Swerdlow AJ, Barber JA, Hudson GV, Cunningham D, Gupta RK, Hancock BW, Horwich A, Lister TA, Linch DC. TI: Risk of second malignancy after Hodgkin's disease in a collaborative british cohort: the relation to age at treatment. SO: J Clin Oncol 2000 Feb;18(3):498. URL: http://www.jco.org/cgi/content/full/18/3/498 PDF: http://www.jco.org/cgi/reprint/18/3/498 Abstract: PURPOSE: To assess long-term site-specific risks of second malignancy after Hodgkin's disease in relation to age at treatment and other factors. PATIENTS AND METHODS: A cohort of 5,519 British patients with Hodgkin's disease treated during 1963 through 1993 was assembled and followed-up for second malignancy and mortality. Follow-up was 97% complete. RESULTS: Three hundred twenty-two second malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone and soft tissue cancers, and of leukemia, increased significantly with younger age at first treatment. Absolute excess risks and cumulative risks of solid cancers and leukemia, however, were greater at older ages than at younger ages. Gastrointestinal cancer risk was greatest after mixed-modality treatment (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to 4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to 47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These risks were generally greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to 43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy). CONCLUSION: Age at treatment has a major effect on risk of second malignancy after Hodgkin's disease. Although absolute excess risks are greater for older patients, RRs of several important malignancies are much greater for patients who are treated when young. The increased risk of gastrointestinal cancers may relate particularly to mixed- modality treatment, and that of lung cancer to chemotherapy as well as radiotherapy; there are also well-known increased risks of breast cancer from radiotherapy and leukemia from chemotherapy. The roles of specific chemotherapeutic agents in the etiology of solid cancers after Hodgkin's disease require detailed investigation. Editor's comments: This is a follow up of the large British series of late effects after treatment for HD. It is important because, unlike most other series, it includes a large number of patients treated with chemotherapy alone. 1693 patients and 18960 person years of follow up were included in the chemo only cohort. In this group, the risk of leukemia and lung cancer were both elevated significantly. This confirms that secondary solid tumors among patients treated for HD may not always be due to radiation treatment. ****************** Lung/Mediastinum: Turrisi 3/00 No Reference Selected ****************** GU: Roach 3/00 No Reference Selected ****************** Radiobiology: Withers 3/00 AU: Alsbeih G, Malone S, Lochrin C, Girard A, Fertil B, Raaphorst GP. TI: Correlation between normal tissue complications and in vitro radiosensitivity of skin fibroblasts derived from radiotherapy patients treated for variety of tumors. SO: Int J Radiat Oncol Biol Phys 2000 Jan 1;46(1):143-52. Abstract: PURPOSE: To assess the relationship between fibroblast intrinsic radiosensitivity in vitro and late reactions of normal tissues in patients treated by definitive radiotherapy for variety of tumors. PATIENTS AND METHODS: Ten patients were selected for this study. They were treated by radical radiotherapy for variety of tumors, including non-Hodgkin's lymphoma, prostate, glottic larynx, anal canal, cervix, bladder, thyroid gland, and tonsil pillar. Five patients did not develop any significant late reactions (normally sensitive group, NS). The other five developed late complications in different normal tissues and organs that proved to be fatal in one patient (clinically hyper-sensitive group, HS). Fibroblast cultures were established from punch skin biopsy and radiosensitivity in vitro was measured. The survival fraction at 2 Gy (SF2) was calculated and compared between the two groups. RESULTS: SF2 ranged between 0.10 and 0.38 with a mean of 0.24. The mean SF2 for each of the NS and the HS groups were 0.31 and 0.17, respectively. The non-parametric rank test of Mann-Whitney shows that the difference between the two groups is statistically significant (p = 0.01). CONCLUSION: This study indicates that the in vitro radiosensitivity of skin fibroblasts is correlated with late complications in different organs and normal tissues following radiotherapy for variety of tumors. It also lends support to the existence of a common genetic component determining the radiosensitivity of cells targeted by the late effects of ionizing radiation. Editor's comments: There is increasing evidence for a spectrum of normal tissue radiosensitivities in a population of patients receiving radiation therapy. This paper reports a small amount of anecdotal data in support of this. The radiosensitivities of fibroblasts cultured from 5 patients classified as being normally radiosensitive (because they experienced the expected severity of normal tissue responses) were compared with those of 5 hypersensitive (HS) patients who developed severe complications. Although the authors state that the 10 patients "all received equivalent treatment regimens in terms of probability to develop severe complications," the data presented in Table 1 show widely diverse total biological doses, including 2 in the HS group who received brachytherapy. The doses ranged from 35 Gy in 20 fractions to a total of 78 Gy given as 20 fractions of 2 Gy plus 38 Gy as low dose rate brachytherapy. There are only 3 patients in each group whose doses are sufficiently similar to permit useful comparisons (total doses of 60, 60 and 66 Gy in 2 Gy fractions in the HS group and 66 Gy in 2 Gy fractions in 3 "normally-sensitive"). Even then, these are tumor doses and not necessarily those received at the sites of the complications. Unfortunately, no information is given to exclude concomitant or sequential chemotherapy. Extracting data for just these 6 patients show that fibroblasts from the 3 HS patients yielded survival rates after 2 Gy (SF2) which were lower than those for the "normally-sensitive" patients, regardless of whether irradiated cells were plated immediately or only after a delay to permit the cells to remain in a quiescent, non-proliferative status for 24 hours, a situation more akin to the in vivo condition of the target cells for late injury. The results are consistent with complications being a reflection of greater intrinsic radiosensitivity: but it may be just an in vitro artifact because a closer inspection of the in vitro data (and the authors are to be commended for including such detail) is that the "survival" of fibroblasts from HS patients exposed to 0 dose, that is, the plating efficiency (PE) is, on average, lower than for the fibroblasts from normally-sensitive patients. Maybe PE would be as useful an assay for relative radiosensitivity as estimating SF2; maybe whatever causes a low PE also leads to a higher radiosensitivity. ****************** Health Services Research: Hayman 3/00 AU: Wolfe J, Grier HE, Klar N, Levin SB, Ellenbogen JM, Salem-Schatz S, Emanuel EJ, Weeks JC. TI: Symptoms and suffering at the end of life in children with cancer. SO: N Engl J Med 2000 Feb 3;342(5):326-33. URL: http://www.nejm.org/content/2000/0342/0005/0326.asp Abstract: BACKGROUND: Cancer is the second leading cause of death in children, after accidents. Little is known, however, about the symptoms and suffering at the end of life in children with cancer. METHODS: In 1997 and 1998, we interviewed the parents of children who had died of cancer between 1990 and 1997 and who were cared for at Children's Hospital, the Dana-Farber Cancer Institute, or both. Additional data were obtained by reviewing medical records. RESULTS: Of 165 eligible parents, we interviewed 103 (62 percent), 98 by telephone and 5 in person. The interviews were conducted a mean (+/-SD) of 3.1+/-1.6 years after the death of the child. Almost 80 percent died of progressive disease, and the rest died of treatment-related complications. Forty-nine percent of the children died in the hospital; nearly half of these deaths occurred in the intensive care unit. According to the parents, 89 percent of the children suffered "a lot" or "a great deal" from at least one symptom in their last month of life, most commonly pain, fatigue, or dyspnea. Of the children who were treated for specific symptoms, treatment was successful in 27 percent of those with pain and 16 percent of those with dyspnea. On the basis of a review of the medical records, parents were significantly more likely than physicians to report that their child had fatigue, poor appetite, constipation, and diarrhea. Suffering from pain was more likely in children whose parents reported that the physician was not actively involved in providing end-of-life care (odds ratio, 2.6; 95 percent confidence interval, 1.0 to 6.7). CONCLUSIONS: Children who die of cancer receive aggressive treatment at the end of life. Many have substantial suffering in the last month of life, and attempts to control their symptoms are often unsuccessful. Greater attention must be paid to palliative care for children who are dying of cancer. Editor's comments: Although only based on data from a single institution, this study suggests that those oncologists caring for children dying of cancer are not doing a particularly good job of relieving a number of distressing symptoms experienced by these patients, including pain and dyspnea. Instead, efforts often appear to be focused on providing relatively aggressive care at the end of their lives. Tremendous strides have been made in providing more appropriate end-of-life care to terminally ill adults patients with cancer. In my opinion, it is now time for us to begin to apply those lessons when caring for terminally ill children as well. Although this article does not specifically examine the utilization of palliative radiation therapy, even if one corrects for the fact that pediatric cancers are much less common, less frequently treated with radiation, and are generally more curable than adult cancers, it is my impression that the proportion of children treated with radiation with purely palliative intent is quite low. If radiation is effective treatment for selected adults with pain and dyspnea, there is no reason to expect that it would be any less effective when administered to children with the similar symptoms. Although radiation seems to be used less and less in pediatric oncology because of concerns about late effects, this is certainly a situation in which that concern becomes irrelevant and in which we potentially have a lot to offer. As strategies are devised to address this issue, I believe we should be relatively aggressive in asserting the benefits of palliative radiation and in making sure that it is included among the solutions to this problem. ****************** Radiation Biophysics: Chen 3/00 Editor's comments: This month's physics contribution deals with multimedia information on IMRT and tomotherapy on the Web. The two websites below describe educational materials of potential interest: URL: http://www.oncolink.upenn.edu/classroom/varian/index.html This website points to educational material on Oncolink. It is a powerpoint presentation describing the steps of treating a head and neck tumor with IMRT, as described by a team at the University of Chicago Medical Center. It gives a good overview of the steps involved. The educational material also is included in a recently distributed CD by a linear accelerator vendor. URL: http://www.madrad.radiology.wisc.edu/ The group at Wisconsin have pioneered the concept of tomotherapy, and this website gives an introduction of this technology. ****************** Brian J. Goldsmith, M.D. Moderator, IROJC