From owner-radoncjc@net.bio.net Mon Feb 7 22:08:03 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 694DF17B40; Mon, 7 Feb 2000 22:07:59 +0000 (GMT) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id A9B9C17B3C; Mon, 7 Feb 2000 22:07:57 +0000 (GMT) To: radoncjc@net.bio.net Subject: February 2000 Internet Radiation Oncology Journal Club (IROJC) Reply-To: radoncjc@net.bio.net Date: Mon, 07 Feb 2000 17:00:57 -0500 From: Brian Goldsmith Message-Id: <20000207220757.A9B9C17B3C@mercury.hgmp.mrc.ac.uk> Sender: owner-radoncjc@net.bio.net Precedence: bulk February 2000 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 57th 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 ----------------------------------------------------- ----------------------------------------------------- RADIATION BIOPHYSICS! With this issue, George Chen Ph.D., Professor and Director, Radiation Biophysics, Massachusetts General Hospital, succeeds Dr. James Purdy as Editor, Radiation Biophysics. Welcome Dr. Chen! ----------------------------------------------------- ----------------------------------------------------- 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 2/00. (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 2/00 AU: Schellong G; Potter R; Bramswig J; Wagner W; Prott FJ; Dorffel W; Korholz D; Mann G; Rath B; Reiter A; Weissbach G; Riepenhausen M; Thiemann M; Schwarze EW. TI: High cure rates and reduced long-term toxicity in pediatric Hodgkin's disease: the German-Austrian multicenter trial DAL-HD-90. The German- Austrian Pediatric Hodgkin's Disease Study Group. SO: J Clin Oncol 1999 Dec;17(12):3736-44. URL: http://www.jco.org/cgi/content/full/17/12/3736 PDF: http://www.jco.org/cgi/reprint/17/12/3736 Abstract: PURPOSE: To further reduce therapy-related late effects in patients with pediatric Hodgkin's disease (HD) while maintaining the high cure rates achieved with vincristine, prednisone, procarbazine, and doxorubicin (OPPA) or OPPA/cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) chemotherapy and involved-field radiotherapy. The risk of testicular dysfunction was addressed by substituting etoposide for procarbazine (OEPA) in the induction therapy for boys. Radiation doses and fields were further reduced. PATIENTS AND METHODS: Three hundred nineteen boys and 259 girls younger than 18 years with previously untreated HD, enrolled onto the study between 1990 and 1995, were allocated to treatment group (TG)1 (early stages), TG2 (intermediate stages), or TG3 (advanced stages). All groups underwent two cycles of OEPA (boys) or OPPA (girls) for induction chemotherapy. TG2 and TG3 continued on additional two or four cycles, respectively, of COPP. Low-dose radiotherapy was given to the initially involved sites, ie, reduced involved fields. RESULTS: Initial response to OPPA or OEPA induction was virtually identical. Eight of 578 patients experienced early progression of HD. Thirty-seven relapses, three secondary tumors, and no secondary leukemias have been recorded, with a median follow-up duration of 5.1 years (maximum, 8.1 years). Thirteen of 578 patients died. The probability of 5-year event-free survival/overall survival is 91%/98% in the total group, 94%/97% with OPPA, and 89%/98% with OEPA induction therapy. Risk factor analysis showed two significant prognostic factors: histologic subtype NS2 and "B" symptoms. OEPA induction therapy, large mediastinal tumor, and age were not significant. Preliminary studies of testicular function indicate a lower risk of germ cell damage than previously documented with OPPA. CONCLUSION: OEPA is a satisfactory alternative to OPPA. Radiotherapy can be confined to involved sites when combined with appropriate chemotherapy. The DAL-HD-90 regimen represents a comprehensive treatment program for all stages of pediatric HD and offers a favorable benefit/risk ratio, combining excellent disease control, moderate acute toxicity, and reduced long-term toxicity. Editor's comments: The German-Austrian Multicenter trial results of DAL-HD-90 are among the best in the world and represent a well reasoned and well conducted combined modality approach to children and adolescents with Hodgkin's Disease. This approach is similar to that used in the United States, with well defined risk groups, although the DAL-HD-90 definition of risk groups differs from that used by others. For example it does not take tumor bulk into account in defining therapy. The study substitutes 2 cycles of Etoposide for 2 cycles of Procarbazine in treatment of males, to reduce or eliminate the risk of infertility. In summary, the 5 year data reported here are excellent. Boys fare less well than girls, although not significantly so, presumably because Etoposide is a less effective agent than Procarbazine. The investigators have not yet seen a difference in survival rates, and the risk of Etoposide induced leukemia is likely small, but not zero. One cannot yet conclude that testicular function will be spared in the OEPA treated patients, as the number of patients evaluated to date is small. However, all in all this combined modality program is an excellent approach to the management of children with Hodgkin's Disease, and once again speaks to the rationale, and excellent outcome when low dose, involved field radiation is added to a limited number of cycles of chemotherapy with low-toxicity. ****************** Head/Neck/Skin: Foote 2/00 AU: Calais G; Alfonsi M; Bardet E; Sire C; Germain T; Bergerot P; Rhein B; Tortochaux J; Oudinot P; Bertrand P. TI: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. SO: J Natl Cancer Inst 1999 Dec 15;91(24):2081-6. URL: http://jnci.oupjournals.org/cgi/content/full/91/24/2081 PDF: http://jnci.oupjournals.org/cgi/reprint/91/24/2081 Abstract: BACKGROUND: We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). METHODS: A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m(2) per day) and 5- fluorouracil (600 mg/m(2) per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. RESULTS: Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P =.02 and.04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). CONCLUSION: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx. Editor's comments: See accompanying editorial by Forastiere and Trotti, Radiotherapy and Concurrent Chemotherapy: a Strategy That Improves Locoregional Control and Survival in Oropharyngeal Cancer, Journal of the National Cancer Institute 91:2065-2066, 1999. ****************** GYN: Petereit 2/00 AU: Petereit DG; Sarkaria JN; Potter DM; Schink JC. TI: High-dose-rate versus low-dose-rate brachytherapy in the treatment of cervical cancer: analysis of tumor recurrence--the University of Wisconsin experience. SO: Int J Radiat Oncol Biol Phys 1999 Dec 1;45(5):1267-74. Abstract: PURPOSE: To retrospectively compare the clinical outcome for cervical cancer patients treated with high-dose-rate (HDR) vs. low-dose-rate (LDR) brachytherapy. METHODS AND MATERIALS: One hundred ninety-one LDR patients were treated from 1977 to 1988 and compared to 173 HDR patients treated from 1989 to 1996. Patients of similar stage and tumor volumes were treated with identical external beam fractionation schedules. Brachytherapy was given in either 1 or 2 LDR implants for the earlier patient cohort, and 5 HDR implants for the latter cohort. For both patient groups, Point A received a minimum total dose of 80 Gy. The linear-quadratic formula was used to calculate the LDR dose-equivalent contribution to Point A for the HDR treatments. The primary endpoints assessed were survival, pelvic control, relapse-free survival, and distant metastases. Endpoints were estimated using the Kaplan-Meier method. Comparisons between treatment groups were performed using the log-rank test and Cox proportional hazards models. RESULTS: The median follow-up was 65 months (2 to 208 months) in the LDR group and 22 months (1 to 85 months) in the HDR group. For all stages combined there was no difference in survival, pelvic control, relapse-free survival, or distant metastases between LDR and HDR patients. For Stage IB and II HDR patients, the pelvic control rates were 85% and 80% with survival rates of 86% and 65% at 3 years, respectively. In the LDR group, Stage IB and II patients had 91% and 78% pelvic control rates, with 82% and 58% survival rates at 3 years, respectively. No difference was seen in survival or pelvic control for bulky Stage I and II patients combined (>5 cm). Pelvic control at 3 years was 44% (HDR) versus 75% (LDR) for Stage IIIB patients (p = 0.002). This difference in pelvic control was associated with a lower survival rate in the Stage IIIB HDR versus LDR population (33% versus 58%, p = 0.004). The only major difference, with regard to patient characteristics, between the Stage IIIB patients was the incidence of hydronephrosis in the HDR vs. LDR group--28% vs. 12%, respectively (p = 0.05). For Stage IIIB patients treated with HDR, our analysis suggested that pelvic control rates improved when the first brachytherapy insertion was performed after the majority of external beam radiotherapy had been delivered. CONCLUSION: Similar outcome was observed for Stage IB and II patients treated with either HDR or LDR brachytherapy-regardless of tumor volume. However, poorer survival and pelvic control rates were observed for Stage IIIB patients treated with HDR brachytherapy. If HDR is used for Stage IIIB patients, our results suggest the majority of external beam radiotherapy should be delivered prior to initiating the brachytherapy to allow for adequate tumor regression. HDR brachytherapy is more convenient for patients, decreases the radiation exposure for health care workers, and should be considered a standard therapy for women with Stage I or II cervical cancer. ****************** GI / Soft Tissue Sarcoma: Tepper 2/00 No Reference Selected ****************** CNS: Bauman 2/00 AU: Prados MD; Scott C; Sandler H; Buckner JC; Phillips T; Schultz C; Urtasun R; Davis R; Gutin P; Cascino TL; Greenberg HS; Curran WJ Jr. TI: A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404. SO: Int J Radiat Oncol Biol Phys 1999 Dec 1;45(5):1109-15. Abstract: PURPOSE: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. RESULTS: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. CONCLUSIONS: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years. Editor's comments: Please see the editorial by Dr. Yung in the same issue as well as the discussion in the paper. I don't have much to add beyond what is addressed by the authors and Dr. Yung. I would echo Dr. Yung's comments that the cooperative groups involved are to be commended for the timely completion of such a large study of a low incidence disease. At the risk of self promotion I would also like to put a plug in for a paper in the November IJROBP: Bauman et al, "Pretreatment Factors Predict Overall Survival for Patients with Low-Grade Glioma: A Recursive Partitioning Analysis" IJROBP, 45(4), 923,1999. While the model suggested by our analysis has limitations given the retrospective databases of low grade glioma which were analysed, it should be possible to perform a similar analysis on some of the large, prospective databases collected as part of the recent EORTC and Intergroup low grade glioma studies. Dr Shaw are you listening? ****************** Breast: Recht 2/00 AU: Fisher B; Dignam J; Wolmark N; Wickerham DL; Fisher ER; Mamounas E; Smith R; Begovic M; Dimitrov NV; Margolese RG; Kardinal CG; Kavanah MT; Fehrenbacher L; Oishi RH. TI: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. SO: Lancet 1999 Jun 12;353(9169):1993-2000. URL: http://www.thelancet.com/newlancet/sub/issues/vol353no9169/article1993.html Abstract: BACKGROUND: We have shown previously that lumpectomy with radiation therapy was more effective than lumpectomy alone for the treatment of ductal carcinoma in situ (DCIS). We did a double-blind randomised controlled trial to find out whether lumpectomy, radiation therapy, and tamoxifen was of more benefit than lumpectomy and radiation therapy alone for DCIS. METHODS: 1804 women with DCIS, including those whose resected sample margins were involved with tumour, were randomly assigned lumpectomy, radiation therapy (50 Gy), and placebo (n=902), or lumpectomy, radiation therapy, and tamoxifen (20 mg daily for 5 years, n=902). Median follow-up was 74 months (range 57-93). We compared annual event rates and cumulative probability of invasive or non- invasive ipsilateral and contralateral tumours over 5 years. FINDINGS: Women in the tamoxifen group had fewer breast-cancer events at 5 years than did those on placebo (8.2 vs 13.4%, p=0.0009). The cumulative incidence of all invasive breast-cancer events in the tamoxifen group was 4.1% at 5 years: 2.1% in the ipsilateral breast, 1.8% in the contralateral breast, and 0.2% at regional or distant sites. The risk of ipsilateral-breast cancer was lower in the tamoxifen group even when sample margins contained tumour and when DCIS was associated with comedonecrosis. INTERPRETATION: The combination of lumpectomy, radiation therapy, and tamoxifen was effective in the prevention of invasive cancer. Editor's comments: This important study shows that tamoxifen reduces the risk of both ipsilateral recurrence and the development of contralateral breast cancers in patients treated with lumpectomy and radiotherapy for DCIS. This is not surprising, given all the information previously known about tamoxifen's effects with regards to these endpoints. The more interesting aspects of this study are to be found in the subgroup analysis. Unlike all prior NSABP breast-conservation studies, patients with unknown or positive margins (defined as tumor at an inked edge) were eligible for this trial, as were patients with negative margins (that is, no tumor at the inked edge, but the actual tumor-free margin width was not measured). The 5-year local failure rate in patients with negative margins who received a placebo was 8.0%. The addition of tamoxifen reduced this rate to 6.3%. However, patients with positive or unknown margins who received the placebo had a local failure rate of 14.7%, compared to 9.0% among patients randomized to tamoxifen. Patient age also was related to the amount of benefit tamoxifen provided in terms of the absolute reduction of local failure. Patients age 49 or younger in the placebo arm had a 16.0% risk of local failure, compared to 10.6% when tamoxifen was given. In contrast, the local failure rate for patients 50 and older was 6.5% in the placebo arm and 5.2% in the tamoxifen arm. (Unfortunately, a 2x2analysis of the impacts of age and margin status together was not performed.) Further analysis of the results of this trial with regards to pathologic findings will be of great interest when central pathologic review is completed. Given the potential toxicities of tamoxifen (which increase with increaing patient age) and the lack of any demonstrated survival advantage in either this trial or the P-1 trial to date, it appears that the case for using tamoxifen selectively for patients with positive margins or those under age 50 is more compelling than the case for its universal use for patients with DCIS treated with radiotherapy. ****************** RES: Hoppe 2/00 AU: Kuppers R; Klein U; Hansmann ML; Rajewsky K. TI: Cellular origin of human B-cell lymphomas. SO: N Engl J Med 1999 Nov 11;341(20):1520-9 URL: http://www.nejm.org/content/1999/0341/0020/1520.asp Editor's comments: An excellent review of the biology of B-cell lymphomas. Readable and well-illustrated. ****************** Lung/Mediastinum: Turrisi 2/00 No Reference Selected ****************** GU: Roach 2/00 AU: Messing EM; Manola J; Sarosdy M; Wilding G; Crawford ED; Trump D. TI: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. SO: N Engl J Med 1999 Dec 9;341(24):1781-8 URL: http://www.nejm.org/content/1999/0341/0024/1781.asp Abstract: BACKGROUND: Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy. METHODS: Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually. RESULTS: After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome. CONCLUSIONS: Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node- positive prostate cancer. Editor's comments: The December 9, 1999 issue of The New England Journal of Medicine brought additional enlightenment regarding the management of node positive prostate cancer. This trial, reported by Messing et al, entitled "Immediate Hormonal Therapy Compared with Observation After Radical Prostatectomy and Pelvic Lymphadenectomy in Men with Node-positive Prostate Cancer" also raises questions. In this small prospective randomized trial, 98 men who underwent radical prostatectomy and lymph node dissections were randomized to receive immediate castration or delayed castration. At the median of 7.1 years, there appeared to be a cause-specific and overall survival advantage in favor of men who received immediate castration. A number of issues must be considered in this trial. PSA was not used as criteria for eligibility or recurrence, or as a reason for initiating androgen therapy in these patients and patients observed to the observation group. When patients died, the cause of death was determined by the treating physician and all patients who were identified as having died of prostate cancer, had progressive widely metastatic and highly symptomatic bone metastasis at the time of death. These combined factors suggest that the number of patients with progressive potentially resulting in death from prostate cancer may have been underestimated. Of interest, a subset analysis of matched patients treated on RTOG trials reach a similar conclusion about the impact of long-term hormonal therapy in the setting of node-positive disease (Roach and Lu unpublished data). Thus these findings are consistent with the results in similar patients treated with radiation therapy and adjuvant hormone therapy. More importantly, this study adds additional support for the significance of early androgen suppression. The median time from randomization to the initiation of hormonal therapy in the observation group was 20 months, (range 2.7 to 69 months); and the median serum PSA, at the start of such treatment was 14 ng/ml. This suggests that delay, as short as one and a half years, associated with a PSA rise in the 10-20 range, may result in a sufficiently large tumor burden that it is too late for hormone therapy to significantly reduce the mortality rate of prostate cancer compared to early intervention. Of course one might argue perhaps waiting 6 months or until the PSA first begins to rise, might not compromise survival. In the absence of a prospective randomized trial, proving this practice may be hazardous to your patient's survival. This study gives further credence to the notion that early hormone therapy should be the standard of care in such high-risk patients. ****************** Radiobiology: Withers 2/00 AU: Svoboda V; Beck-Bornholdt HP; Herrmann T; Alberti W; Jung H, TI: Late complications after a combined pre and postoperative (sandwich) radiotherapy for rectal cancer. SO: Radiother Oncol 1999 Dec;53(3):177-87. Abstract: BACKGROUND AND PURPOSE: The purpose of this study was to analyse the treatment related side effects, the outcome and the prognostic significance of clinical parameters in two groups of patients with rectal cancer receiving either preoperative or pre and postoperative radiotherapy after radical resection. The authors of this study were not involved in the radiation treatments. PATIENTS AND METHODS: From 1986 to 1990, 63 patients received a combined pre and postoperative (sandwich) Gy each applied within 2 or 3 days. Postoperative irradiation consisted mostly of 15 x 2 Gy (31 patients) but the range was 20-40 Gy. The results were compared with those on 73 patients who only received preoperative radiotherapy in the same time period. The distribution of prognostic factors was not very different between treatment groups. Out of 63 patients in the sandwich group, 22 received concurrent chemotherapy and 18 also received radiotherapy to the liver. Radical surgery usually followed on the day after the last preoperative radiotherapy session. Median follow-up of survivors was 6 years. RESULTS: Local tumour control was 88% after 5 years and 84% after 8 years in the sandwich group, and 90 and 85%, respectively, in the preoperative radiotherapy group. Thus, tumour control was similar for the two radiotherapy regimens applied. However, the percentage of patients suffering from one or more complications after 5 years was 84% in the sandwich and 17% in the preoperative radiotherapy group. The incidence of severe late complications (grade > or = 3) was recorded as a function of time after start of treatment. In the sandwich group the actuarial rates of late complications at 5 years (and the median time to diagnosis) were 53% (27 months) for anorectum, 43% (37 months) for bladder, 28% (51 months) for bone, 19% (36 months) for dermis, 47% (48 months) for ileum, 41% (32 months) for lymphatic and soft tissue, and 44% (53 months) for ureters. CONCLUSIONS: Severe late reactions did not occur within a certain period of time, but continued to appear for at least 10 years after radiotherapy. Sandwich therapy, as given in this series, did not appear to give a greater tumour control than preoperative radiotherapy alone, whereas the rate of complications was drastically enhanced. Thus, the rationale of a sandwich therapy with a long time interval between surgery and postoperative irradiation appears questionable. Editor's comments: This careful analysis of a clinical fractionation misadventure 10-14 years ago is a reminder of several radiobiologic principles. Large fraction sizes (5 Gy in this case) can amplify the total biological doses, and cause a steep rate of increase of complications, especially in late-responding tissues. This adverse effect is exacerbated by large treatment volumes and short interfraction intervals and is not associated with a comparable increase in effect on the tumor. Chemotherapy can also worsen sequelae. Of particular importance, they show that late effects are late effects - this actuarial incidence still climbing at 8 years. The potential injuries from aggressive new strategies (e.g. of accelerated fractionation, or chemoradiation, or even in the high dose volumes of IMRT) may be smoking guns. ****************** Health Services Research: Hayman 2/00 No Reference Selected ****************** Radiation Biophysics: Chen 2/00 AU: Booth JT; Zavgorodni SF. TI: Set-up error & organ motion uncertainty: a review. SO: Australas Phys Eng Sci Med 1999 Jun;22(2):29-47. Abstract: Conformal radiotherapy allows improvement in the treatment outcome due to increased targeting accuracy through advanced beam shaping techniques to precisely conform radiation dose to the geometry of the tumour. Treatment set-up and organ motion uncertainties are unavoidable factors that are limiting increases in accuracy and have to be accounted for in conformal treatment planning. The magnitudes of set-up errors and organ motion uncertainties for specific sites, and using various set-up techniques, have been quantified in the literature. However, the parameters used with these measurements and the presentation of the data has differed between studies for the same site. The purpose of this paper is to analyse and combine the published material into a uniform format and to display typical reported values of set-up and organ motion uncertainties. Values measured under similar conditions were averaged across studies. The results of this analysis illustrate (1) variability in the parameters used for measurements across studies, (2) typical motion ranges of the prostate, kidneys, liver and diaphragm, (3) typical means and standard deviations for set- up errors associated with the prostate, pelvis, brain, head and neck, thorax, rectum and breast and (4) a brief review of the common methods to lower or account for these uncertainties. Editor's comments: This is a good, up to date review of the literature on organ motion and setup error, variables that are important to understand when implementing conformal / IMRT treatments. Because averages are calculated across data sets from different articles, the most appropriate values for margins for a specific immobilization technique at a given institution should be derived from internal departmental motion studies. However, these data provide a good perspective of uncertainties for comparison. ****************** Brian J. Goldsmith, M.D. Moderator, IROJC From owner-radoncjc@net.bio.net Tue Feb 8 23:30:26 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 9DEE817BE3; Tue, 8 Feb 2000 23:30:23 +0000 (GMT) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id 761E517A8D; Tue, 8 Feb 2000 23:30:22 +0000 (GMT) To: radoncjc@net.bio.net Subject: IROJC GYN February 2000 Addendum Reply-To: radoncjc@net.bio.net Date: Tue, 08 Feb 2000 18:16:31 -0500 From: Brian Goldsmith Message-Id: <20000208233022.761E517A8D@mercury.hgmp.mrc.ac.uk> Sender: owner-radoncjc@net.bio.net Precedence: bulk GYN: Petereit 2/00 Addendum Dr. Petereit's comments were accidently not included in the February 2000 IROJC posting yesterday. Below is the complete GYN 2/00 citation, abstract, and Editor's comments. Thank you for your patience. Brian Goldsmith, M.D. Moderator, IROJC ------------------------------------------- GYN: Petereit 2/00 AU: Petereit DG; Sarkaria JN; Potter DM; Schink JC. TI: High-dose-rate versus low-dose-rate brachytherapy in the treatment of cervical cancer: analysis of tumor recurrence--the University of Wisconsin experience. SO: Int J Radiat Oncol Biol Phys 1999 Dec 1;45(5):1267-74. Abstract: PURPOSE: To retrospectively compare the clinical outcome for cervical cancer patients treated with high-dose-rate (HDR) vs. low-dose-rate (LDR) brachytherapy. METHODS AND MATERIALS: One hundred ninety-one LDR patients were treated from 1977 to 1988 and compared to 173 HDR patients treated from 1989 to 1996. Patients of similar stage and tumor volumes were treated with identical external beam fractionation schedules. Brachytherapy was given in either 1 or 2 LDR implants for the earlier patient cohort, and 5 HDR implants for the latter cohort. For both patient groups, Point A received a minimum total dose of 80 Gy. The linear-quadratic formula was used to calculate the LDR dose-equivalent contribution to Point A for the HDR treatments. The primary endpoints assessed were survival, pelvic control, relapse-free survival, and distant metastases. Endpoints were estimated using the Kaplan-Meier method. Comparisons between treatment groups were performed using the log-rank test and Cox proportional hazards models. RESULTS: The median follow-up was 65 months (2 to 208 months) in the LDR group and 22 months (1 to 85 months) in the HDR group. For all stages combined there was no difference in survival, pelvic control, relapse-free survival, or distant metastases between LDR and HDR patients. For Stage IB and II HDR patients, the pelvic control rates were 85% and 80% with survival rates of 86% and 65% at 3 years, respectively. In the LDR group, Stage IB and II patients had 91% and 78% pelvic control rates, with 82% and 58% survival rates at 3 years, respectively. No difference was seen in survival or pelvic control for bulky Stage I and II patients combined (>5 cm). Pelvic control at 3 years was 44% (HDR) versus 75% (LDR) for Stage IIIB patients (p = 0.002). This difference in pelvic control was associated with a lower survival rate in the Stage IIIB HDR versus LDR population (33% versus 58%, p = 0.004). The only major difference, with regard to patient characteristics, between the Stage IIIB patients was the incidence of hydronephrosis in the HDR vs. LDR group--28% vs. 12%, respectively (p = 0.05). For Stage IIIB patients treated with HDR, our analysis suggested that pelvic control rates improved when the first brachytherapy insertion was performed after the majority of external beam radiotherapy had been delivered. CONCLUSION: Similar outcome was observed for Stage IB and II patients treated with either HDR or LDR brachytherapy-regardless of tumor volume. However, poorer survival and pelvic control rates were observed for Stage IIIB patients treated with HDR brachytherapy. If HDR is used for Stage IIIB patients, our results suggest the majority of external beam radiotherapy should be delivered prior to initiating the brachytherapy to allow for adequate tumor regression. HDR brachytherapy is more convenient for patients, decreases the radiation exposure for health care workers, and should be considered a standard therapy for women with Stage I or II cervical cancer. Editor's comments: We just published the University of Wisconsin Experience comparing HDR to LDR brachytherapy in the management of cervical cancer. This paper is an update of the initial study with significantly more patients in the HDR group. The earlier report concluded that both forms of brachytherapy produced equivalent results. In this update stage I and II patients also had similar results, however, the stage IIIB patients did much worse when treated with HDR brachytherapy. Potential reasons for this include "reverse stage migration", timing of the brachytherapy and the method of brachytherapy. What I mean by "reverse stage migration" is this: the senior gynecologic oncologist tended to call any patient with disease tethered to the sidewall as IIIB, whereas gynecologic oncologists that later staged the patients would classify these patients as IIB. In fact, the stage IIB and IIIB LDR patients, who were all managed by the senior gynecologic oncologist, had identical outcomes -- 3 year pelvic control rates of 78% and 75%. As a resident training under the senior gynecologic oncologist, achieving optimal geometry for the bulky IIIB patients treated with HDR brachytherapy was often very difficult. The institutional policy was to perform the first HDR implant as soon as possible so as to avoid treatment prolongation. Since the IIIB patients treated with HDR appeared to do worse when compared to the LDR cohort, an analysis was performed to determine pelvic control rates as a function of the median external beam dose at the first insertion. Tumor bulk was taken into account by stratifying on the tumor burden score. Although the data presented in Figure 6 did not reach statistical significance, there was a suggestion that waiting longer for adequate tumor regression improved pelvic control rates. Although the complication rates were not given in the manuscript, they were as follows: Actuarial Complications (Greater than or equal to Grade 3) By Stage At 3 Years. Technique (Patient #) Complication Rate Overall HDR (173) 15% Overall LDR (191) 12% Stage IB HDR (59) 16% Stage IB LDR (76) 9% Stage II HDR (64) 14% Stage II LDR (65) 9% Stage IIIB HDR (50) 16% Stage IIIB LDR (50) 20% Actuarial Complications (Greater than or equal to Grade 3) By Organ Site At 3 Years Overall GU Rectum Small Bowel LDR 12% 2.6% 5.6% 5.4% HDR 15% 3.0% 4.6% 9.5% This data will eventually appear in a future publication. The University of Wisconsin Experience is one of the largest North American databases published to date. While there are limitations to retrospective analyses, every attempt was made to carefully scrutinize these patient cohorts in order to accurately report the data. My take home message from these data set are as follows: 1) HDR and LDR produce very similar outcome for stage I and II patients 2) timing of the implant is critical; as in LDR brachytherapy the first implant should be done only after adequate tumor regression 3) complication rates should not be under-emphasized when counseling patients - whether LDR or HDR is used. Although our data suggested that stage IIIB patients fared worse when HDR was used, I do not believe that HDR brachytherapy was the cause for poorer outcome. However, my personal bias would be to use LDR brachytherapy for stage IIIB patients that have very poor anatomy: conical shaped vaginas which have obliterated fornices as the result of tumor infiltration. With these patients cylinders need to be used rather that ovoids. This sets up a "double jeopardy situation" in that packing cannot be used and the dose cannot be thrown out much further than the vaginal surface, otherwise normal tissue tolerance is exceeded. It is in these situations where LDR brachytherapy is more forgiving. This is also a situation where some institutions favor an interstitial implant.