PORTEC-2: B. Pras Groningen

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1 PORTEC-2: Postoperative Radiation Therapy for Endometrial Carcinoma a multicenter randomised phase III trial comparing external beam radiation and vaginal brachytherapy Study coordinator: C.L. Creutzberg Leiden Protocol Committee: J.G. Aalders Groningen A. Ansink Rotterdam H. Beerman Rotterdam K.A.J. De Winter Tilburg M.E. van Eijkeren Utrecht J.J. Jobsen Enschede P.C.M. Koper Rotterdam L.C.H.W. Lutgens Maastricht M.L.M. Lybeert Eindhoven B. Pras Groningen I.M. Schulz Utrecht A. Slot Leeuwarden V.T.H.B.M. Smit Leiden E. van der Steen-Banasik Arnhem Trial Statistician: W.L.J. van Putten Rotterdam Quality of Life: A.H. Zwinderman Amsterdam Data management: IKW Trial Office, C-9-P, LUMC, P.O. Box 9600, 2300 RC Leiden Tel: Fax: and Dept of Statistics, LUMC (Promise, web program) Approved: CME LUMC (P01.146) NKB-CKTO (CKTO ) Final Version: December 2001

2 Contents 1. Introduction and summary of the literature Introduction The PORTEC trial Balancing locoregional control and risk of adverse effects Vaginal brachytherapy Quality of life References Study objectives Study design Patient selection Inclusion criteria Exclusion criteria Staging and Treatment Staging Surgery Radiotherapy External beam radiation Vaginal brachytherapy Pathology Histopathologic evaluation Central pathology review Follow-up Quality of life assessment Registration and randomisation Statistical considerations Number of patients and power calculation Stopping rule and interim analysis Statistical analysis Ethics Trial Insurance Publication policy List of participating centers Page Appendices A. Trial summary B. FIGO staging system C. Performance status (WHO) D. Histologic classification of the International Society of Gynecologic Pathologists FIGO histologic grading system E. EORTC/RTOG radiation morbidity scoring system F. Quality of life questionnaire G. Patient information H. Forms and procedures for collecting data

3 1. Introduction and summary of the literature 1.1. Introduction Endometrial carcinoma is the most common gynaecological cancer, with an annual incidence in Western countries of per women. The large majority (75 80%) of endometrial cancers is diagnosed at an early stage (International Federation of Gynecology and Obstetrics (FIGO) stage 1, Appendix B). The most significant prognostic factors are tumor stage, histologic grade, depth of myometrial invasion, and age. Surgery, consisting of a total abdominal hysterectomy and bilateral salpingo oophorectomy (TAH BSO) is the cornerstone of treatment. Postoperative pelvic radiotherapy (RT) is considered if risk factors are present, that is, deep myometrial invasion (50% or more of the myometrial width) and/or grade 2 or 3 histology. Patients with stage I endometrial carcinoma, treated with TAH BSO followed by postoperative RT have a 5 year overall survival of 80 90%, a 5 year cancer specific survival of 90 95% and a 5-year locoregional recurrence rate of 4 8% (1-7). The subgroup of patients with grade 3 tumors with deep ( 50%) myometrial invasion, however, have a considerably higher risk of locoregional and, most notably, distant relapse (1,2,8,9). In the randomised study reported by Aalders et al (1), 540 women who had undergone TAH BSO and postoperative vaginal RT (60 Gy) were randomly assigned to additional pelvic RT or observation. Although pelvic RT reduced vaginal and pelvic recurrence rates (2% versus 7% in the control group), more distant metastases were found in the pelvic RT group (10% versus 5%), and survival was not improved (89% versus 91% 5 year survival). Only the subgroup with grade 3 tumors with deep ( 50%) invasion showed both improved local control and survival after additional pelvic RT. Most locoregional relapses are located in the vagina, mainly in the vaginal vault. In previously unirradiated patients reported salvage rates for isolated vaginal relapse are 40 80% (6,10-15). The salvage rate of extravaginal pelvic relapse is low, ranging from <5% for patients who have received previous pelvic RT, to 20 30% in those not previously irradiated (6,11,12,15,16). In the GOG staging study (17), the risk of pelvic node metastases in surgical stage I endometrial carcinoma was shown to be less than 10%, except for the subgroup with grade 3 tumors with deep (outer 33%) myometrial invasion, in which the risk amounted to 18% The PORTEC trial Based on the rationale that (1) the locoregional relapse rate after TAH-BSO and RT tailored to prognostic factors is low, (2) the efficacy of RT has never been established in a randomised trial, (3) lymphadenectomy studies (17,18) show an incidence of pelvic lymph node involvement in surgical stage I endometrial carcinoma of less than 10%, and (4) the salvage rate of vaginal relapses in 3

4 previously unirradiated patients is high, the multicenter prospective randomised PORTEC-trial was designed to determine the role of postoperative pelvic RT in FIGO stage I endometrial carcinoma. Patients with grade 1 tumors with deep ( 50%) myometrial invasion, grade 2 tumors with any invasion, or grade 3 tumors with superficial (<50%) invasion were randomly assigned to either postoperative pelvic RT or no further treatment. The results of the PORTEC-trial have recently been published (19). Postoperative pelvic RT significantly reduced the 5-year actuarial risk of locoregional relapse from 14% in the control group to 4% in the RT group (p<0.001). This difference in locoregional recurrence did, however, not translate into a survival benefit: the 5-year overall survival rates were 85% in the control group and 81% in the RT group (p=0.31). The 5-year endometrial carcinoma related death rates were 9% in the RT group and 6% in the control group, and the rates of distant metastases were 8% and 6%. The majority of the locoregional recurrences were located in the vagina (10% in de control group and 2% in de RT group), over 80% of which were found in or near the vaginal vault. The survival after (any first) relapse was significantly (p=0.02) better in the control group (51% 3-year survival, as compared to 19% in de RT group). The survival after vaginal relapse was 71% at 3 years. Pelvic RT increased treatment related morbidity (26% (predominantly grade 1) complications in the RT group and 5% in the control group), and caused 3% serious (grade 3) bowel complications at 5 years. Multivariate analysis showed that age below 60 years was a significant favourable prognostic factor, both for the risk of locoregional relapse and endometrial carcinoma related death. The most significant prognostic factors which were associated with local control were pelvic RT (p<0.0001) and age below 60 years (p=0.003), while grade 3 histology and deep ( 50%) myometrial invasion were both associated with an increased risk of locoregional recurrence which did not reach statistical significance (p=0.11). For endometrial carcinoma related death, grade 3 histology (p=0.0008) and age 60 and over (p=0.02) were the significant adverse prognostic factors. The central pathology review of the PORTEC study revealed a considerable shift from grade 2 to grade 1 tumors. Initially, 21% of the specimens had been assigned grade 1, 68% grade 2 and 11% grade 3, while at systematic review according to the FIGO grading criteria 60% were diagnosed grade 1, 32% grade 2, and 8% grade 3. Interestingly, the revised grade had no better predictive power than the original grade. Grade 1 and 2 did not have any difference in prognostic significance, while grade 3 was a strong adverse prognostic factor for endometrial carcinoma related death. In view of the limited clinical significance and reproducibility of the intermediate grade, Lax et al (20) proposed a two-tiered grading system, which discriminates between favourable and poor prognostic groups. This two-tiered grading system is currently being tested on the PORTEC review specimens (see also section 7.2). 4

5 The subgroup of patients with stage IB grade 2 disease, and the subgroup with age below 60 years both had a very favourable outcome: their 5-year risks of locoregional relapse were 5% and 4%, respectively. The remaining PORTEC- high risk group of patients aged 60 and over with stage IB grade 3 or stage IC grade 1 or 2 disease had a 5-year actuarial risk of vaginal or pelvic recurrence of 19% without RT (14% vaginal; 5% pelvic), as compared to 5% with RT (3% vaginal, 2% pelvic). Again, no survival benefit was observed Balancing locoregional control and risk of adverse effects It can be concluded from the PORTEC results that the role of pelvic RT for stage 1 endometrial carcinoma is restricted to the reduction of the risk of locoregional relapse, without a survival benefit. Thus, RT cannot be considered indicated if the a priori risk of locoregional recurrence at 5 years is less than 10%, as was the case for the subgroups with either stage IB grade 2 disease (5%), or with age below 60 years (4%). As a result of these findings, in The Netherlands the indication for RT was abandoned for patients with stage IB grade 2 disease and for patients younger than 60 years (except for stage IC grade 3 cases, who had not been included in the trial). Pelvic RT is now considered indicated in stage 1 endometrial cancer in the presence of at least 2 of the following 3 risk factors: grade 3, age 60 and over, outer 50% myometrial invasion. For these remaining subgroups of endometrial cancer it can still be debated, in view of the absence of a survival benefit, if external beam RT is indicated (21). However, pelvic RT significantly reduces the risk of vaginal and pelvic relapse and improves the rates of disease-free survival. The occurrence of a relapse and the subsequent treatment with side effects and increased anxiety are very stressful, and the emphasis is on optimal local control at the first treatment for most cancer sites. Many authors, especially from the U.S., advocate lymphadenectomy as an additional staging procedure in endometrial cancer patients (18,22-24). They state that in the absence of lymph node metastases RT can be omitted, and that cure rates might even be increased after lymphadenectomy. However, these retrospective series are subject to considerable selection bias. For example, the mean age in the study by Mohan et al (23) was 58 years, in contrast to 67 years in the PORTEC study, while age below 60 was shown to be a major favourable prognostic factor. The rates of vaginal and pelvic relapse after lymphadenectomy appear to be similar to those in the control arm of the PORTEC study without lymphadenectomy. In the randomised GOG 99 trial, which has until now only be published as an abstract (25), all patients were treated with TAH-BSO with lymphadenectomy. Patients without pelvic node metastases were randomised to pelvic ERT or no further treatment. The 2-year relapse free survival rates were 88% in the control group (17 locoregional recurrences in 200 patients) and 96% in the RT group (3 recurrences in 190 patients). 5

6 These results are strikingly similar to those obtained in the PORTEC study. However, the rate of severe complications was 8%. Most gynaecologic oncologists consider ERT or vaginal brachytherapy indicated in surgically staged patients if risk factors are present, to ensure optimal local control (26). As the rates of locoregional recurrence were similar in the control groups of the GOG-99 (with lymphadenectomy) and the PORTEC study (without lymphadenectomy), in view of the low pelvic relapse rate in the control group of the PORTEC study (4%), and of the increased rate of severe complications (8% in the GOG trial), lymphadenectomy cannot be considered standard treatment for stage 1 endometrial carcinoma. The ongoing randomised MRC-ASTEC study will, hopefully, provide definite answers as to the role of lymphadenectomy in stage 1 endometrial cancer Vaginal brachytherapy The question can be raised whether vaginal brachytherapy can be used instead of ERT to obtain equally high local control rates with less side effects and, consequently, to obtain optimal diseasefree and overall survival rates as well as best quality of life. Literature data from (mostly retrospective) studies which used vaginal brachytherapy alone in stage 1 endometrial cancer showed the 5-year risk of vaginal relapse to be 0-7% (1,10,18,27-34). Even with modest doses of vaginal brachytherapy, in most series vaginal control rates of over 95% were reported. Pelvic and distant failure rates and overall survival were similar to those of patients treated with surgery alone. However, most studies included only or mainly low risk (grade 1-2 with <50% invasion) patients. Traditionally, vaginal brachytherapy involves low-dose-rate (LDR) brachytherapy using vaginal cylinders. Eltabbakh et al (27) reviewed the outcome of 303 low risk patients treated with TAH- BSO and LDR brachytherapy using vaginal cylinders delivering 30 Gy specified at 5 mm depth (52 Gy at the vaginal surface). The 5- and 10-year vaginal control rates were 100%, the 10-year DFS 97.8%. Recurrences were at distant sites with pelvic involvement in 2 of the 6 patients. Severe radiation therapy complications occurred in 2.1% of the patients. Of note, this study included 29 otherwise low-risk patients with malignant peritoneal cytology who were additionally treated with 1 year of progesterone therapy. The 5- and 10-year DFS in this group were 100%. Bond et al (10) compared vaginal brachytherapy (50 Gy LDR, specified at the mucosal surface, or Gy HDR in 5 daily insertions), with no further treatment after TAH-BSO in 1703 stage 1 patients. Vaginal brachytherapy eliminated vaginal recurrence in non-invasive tumors, and halved the vaginal recurrence rate from 8.3 to 4.3% in tumors with myometrial invasion. No difference was seen in the rates of pelvic (7.6%) and distant failure (8%), or of 5-year overall survival (80%). HDR brachytherapy to 40 Gy gave more complications and no better effect than 30 Gy HDR or than 6

7 LDR. Rose et al (28) reported no apparent benefit of 60 Gy LDR brachytherapy (specified at the surface, equivalent to 40 Gy at 5 mm) in 146 low-risk patients, who had a vaginal recurrence rate of 4.8%. High risk-stage 1 and stage 2 patients were included in some LDR-studies. Elliott et al (29) reported treatment outcome in 811 stage I and 116 stage 2 endometrial cancer patients, and compared 145 patients treated to the vaginal vault (1960s-early 1970s) and 290 patients treated to the whole vagina (from mid 1970s onwards) with 492 patients treated with surgery alone. The brachytherapy dose was 60 Gy LDR at the surface, comparable to 30 Gy at 1 cm. There were 40 vaginal recurrences, with 10-year rates of 2.8% in low risk, 9.3% in high risk-stage 1 patients and 11.2% in stage 2 patients. Only 8 of the 435 patients treated with brachytherapy had a vaginal recurrence, 4 of which were stage 2 patients treated to the vault only. The rate of vaginal control was highest (99%) in patients treated to the entire vaginal length; however, the group treated to the vault had more high risk patients. In the randomised trial by Aalders et al (1), 261 of the 518 stage 1 patients had highrisk features (grade 3 and/or outer 50% invasion). In the control group, treated with 60 Gy LDR vaginal brachytherapy specified at the surface, the vaginal and pelvic recurrence rate was 7%, as compared to 2% in the patients treated with ERT after brachytherapy. In the randomised COSA study (18) 207 surgically staged (pn0) patients were treated with 60 Gy brachytherapy (specified at the surface). The rates of vaginal and pelvic recurrence were 1% and 3.4%, respectively. LDR treatment requires hospitalisation and bed rest for hours, with a risk of life-threatening (cardiovascular, thrombo-embolic and/or pulmonary) events. Dusenberry et al (35) reported such events in 6.4% (21 of 327 patients), of which 5 were fatal. The advantages of high dose rate (HDR) brachytherapy (increased patient convenience, no hospitalisation with bed rest, decreased risk of acute events, improved stability of the applicators during treatment, possibility of optimisation of dose distributions) prompted its use in many centers. Despite the theoretical biologic disadvantages of HDR brachytherapy, reported vaginal control and complications rates for vaginal HDR brachytherapy are comparable to those of LDR (36). Pearcey and Petereit (31) reviewed the results of HDR-brachytherapy in stage 1 endometrial cancer patients and concluded that a LQED up to 42 Gy at 5 mm (for example, 35 Gy HDR to the surface or 21 Gy to 5 mm depth in 3 fractions) provided local control rates of 98% and over. The use of higher doses did not lead to improved local control, while complication rates were increased. Many different HDR treatment schemes were used. Chadha et al (32) and Weiss et al (33) both prescribed 3 fractions of 7 Gy (specified, however, at 5 mm depth and at the surface, respectively) to the upper ½ - 2/3 vagina in 3 weeks, and found excellent vaginal control rates. In both series high risk patients were included: in Weiss series 44 out of 122 patients treated with TAH-BSO and vaginal brachytherapy had high risk-stage 1 or stage 2 disease, and in Chadha s study 38 of 124 surgically staged patients were high risk. The vaginal 7

8 control rates were 98.4 and 100%. Pelvic and distant relapses were mostly found in high risk-stage 1 and stage 2 patients, yielding 5-year DFS rates of 94% and 74%, respectively (33). Anderson et al (34) even proposed a dose level as low as 3 fractions of 5 Gy (at 5 mm) in a similar group of 102 surgically staged patients of which 41 had high risk features. They reported a 98% local control rate and 5-year DFS of 93%. The treatment schedule reported by Petereit et al (30), using ovoids and prescribing 2 fractions of 16.2 Gy HDR (specified at the vaginal surface) one week apart, yielded equivalent vaginal control and complication rates. Vaginal recurrences are mainly located in the vaginal vault and upper vagina, with a ratio of proximal to distal recurrences of 4:1 (18,29). Several authors recommend treating only the upper half of the vagina, as this is associated with lower complication rates (vaginal stenosis and fistula) than when treating the entire length of the vagina. Although most authors use vaginal cylinders treating the upper 1/2-2/3 of the vagina, others claim that vaginal ovoids have the advantage of providing a better dose distribution around the vaginal vault with lower doses to the bladder and rectum (30,36). In summary, moderate, convenient dose fractionation schedules of vaginal brachytherapy provide very high vaginal control rates (of over 95%), and very low morbidity rates. The use of higher doses increases the risk of side effects, and does not further increase the vaginal control rates. Based on these data, optimal LDR and HDR dose schedules seem to be those, which give an equivalent of Gy to the mucosal surface of the upper ½ of the vagina. Typical examples are LDR 30 Gy, specified at 5 mm depth, at a dose rate of cgy/hr, in one session of 2-3 days, or HDR 21 Gy, specified at 5 mm depth, in 3 fractions of 7 Gy each 1 week apart Quality of life There are very few published data concerning quality of life issues for patients with endometrial cancer. Most reports on quality of life (QOL) after treatment for gynaecological cancers involve patients with cancer of the cervix, who undergo more extensive surgery and/or radiotherapy. Cancer patients in general experience many problems with a negative influence on their QOL. These problems can be caused by the disease itself, but also by the side effects of the treatment. The majority of women with endometrial cancer are cured but the treatment may induce alterations in functional status, activity and family relationship and thereby affect health related QOL. Hueguenin et al (37) prospectively studied QOL in elderly patients (aged 75 years or over) with endometrial cancer, treated with radiotherapy. In their study the EORTC QLQ-C30 (38) was used. They found a more or less constant state of good QOL, despite an actuarial severe complication rate of 7% at 3 years. Bye et al (39,40) used the EORTC QLQ-C36 to investigate QOL of patients who had undergone pelvic RT for cancer of the endometrium or cervix. The patients scored lower than the 8

9 general population on role functioning and higher on diarrhoea. Substantial pain and diarrhoea were associated with a deterioration in health-related QOL. The scores on social functioning and the global health/quality of life were similar to those in the general population. Klee et al (41,42) used the EORTC QLQ-C30 and additional specific questions to assess the psychological and social reactions and physical symptoms of women with advances stages of cervical cancer during and after radiotherapy. They found that many patients experienced physical, psychological and social consequences at the end of treatment and continued to think about their illness and treatment throughout the 2-year study period, but found it increasingly hard to share their worries. Their score on overall QOL never reached that of the controls. 2. References 1. Aalders J, Abeler V, Kolstad P, et al. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980;56: Meerwaldt JH, Hoekstra CJ, van Putten WL, et al. Endometrial adenocarcinoma, adjuvant radiotherapy tailored to prognostic factors. Int J Radiat Oncol Biol Phys 1990;18: Grigsby PW, Perez CA, Kuten A, et al. Clinical stage I endometrial cancer: prognostic factors for local control and distant metastasis and implications of the new FIGO surgical staging system. Int J Radiat Oncol Biol Phys 1992;22: DiSaia PJ, Creasman WT, Boronow RC, et al. Risk factors and recurrent patterns in Stage I endometrial cancer. Am J Obstet Gynecol 1985;151: Brady LW, Perez CA, Bedwinek JM. Failure patterns in gynecologic cancer. Int J Radiat Oncol Biol Phys 1986;12: Poulsen MG, Roberts SJ. Prognostic variables in endometrial carcinoma. Int J Radiat Oncol Biol Phys 1987;13: Irwin C, Levin W, Fyles A, et al. The role of adjuvant radiotherapy in carcinoma of the endometrium- results in 550 patients with pathologic stage I disease. Gynecol Oncol 1998;70: Burke TW, Heller PB, Woodward JE, et al. Treatment failure in endometrial carcinoma. Obstet Gynecol 1990;75: Morrow CP, Bundy BN, Kurman RJ, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991;40: Bond WH. Early uterine body carcinoma: has post-operative vaginal irradiation any value? Clin Radiol 1985;36: Ackerman I, Malone S, Thomas G, et al. Endometrial carcinoma--relative effectiveness of adjuvant irradiation vs therapy reserved for relapse. Gynecol Oncol 1996;60: Poulsen MG, Roberts SJ. The salvage of recurrent endometrial carcinoma in the vagina and pelvis. Int J Radiat Oncol Biol Phys 1988;15: Hoekstra CJ, Koper PC, van Putten WL. Recurrent endometrial adenocarcinoma after surgery alone: prognostic factors and treatment. Radiother Oncol 1993;27:

10 14. Curran WJ, Jr., Whittington R, Peters AJ, et al. Vaginal recurrences of endometrial carcinoma: the prognostic value of staging by a primary vaginal carcinoma system. Int J Radiat Oncol Biol Phys 1988;15: Sears JD, Greven KM, Hoen HM, et al. Prognostic factors and treatment outcome for patients with locally recurrent endometrial cancer. Cancer 1994;74: Salazar OM, Feldstein ML, DePapp EW, et al. Endometrial carcinoma: analysis of failures with special emphasis on the use of initial preoperative external pelvic radiation. Int J Radiat Oncol Biol Phys 1977;2: Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;60: COSA-NZ-UK endometrial cancer study group. Pelvic lymphadenectomy in high risk endometrial cancer. Int J Gynecol Cancer 1996;6: Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Lancet 2000;355: Lax SF, Kurman RJ, Pizer ES, et al. A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis. Am J Surg Pathol 2000;24: Burger MP. Management of stage 1 endometrial carcinoma. Postoperative radiotherapy is not justified in women with medium risk disease. BMJ 2001;322: Orr JW. Surgical staging of endometrial cancer: does the patient benefit? Gynecol Oncol 1998;71: Mohan DS, Samuels MA, Selim MA, et al. Long-term outcomes of therapeutic pelvic lymphadenectomy for stage I endometrial adenocarcinoma. Gynecol Oncol 1998;70: Fanning J, Nanavati PJ, Hilgers RD. Surgical staging and high dose rate brachytherapy for endometrial cancer: limiting external radiotherapy to node-positive tumors. Obstet Gynecol 1996;87: Roberts J.A, Brunetto V.L., and Keys, H. M. A phase III randomized study of surgery vs. surgery plus adjunctive radiation therapy in intermediate risk endometrial adenocarcinoma (GOG#99). Gynecol Oncol 1998;68:135 (Abstract) 26. Naumann RW, Higgins RV, Hall JB. The use of adjuvant radiation therapy by members of the Society of Gynecologic Oncologists. Gynecol Oncol 1999;75: Eltabbakh GH, Piver MS, Hempling RE, et al. Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: report of a prospective trial. Int J Radiat Oncol Biol Phys 1997;38: Rose PG, Tak WK, Fitzgerald TJ, et al. Brachytherapy for early endometrial carcinoma: a comparative study with long-term follow-up. Int J Gynecol Cancer 1999;9: Elliott P., Green D., Coates A., et al. The efficacy of postoperative vaginal irradiation in preventing vaginal recurrence in endometrial cancer. Int J Gynecol Cancer 1994;4: Petereit DG, Tannehill SP, Grosen EA, et al. Outpatient vaginal cuff brachytherapy for endometrial cancer. Int J Gynecol Cancer 1999;9: Pearcey RG, Petereit DG. Post-operative high dose rate brachytherapy in patients with low to intermediate risk endometrial cancer. Radiother Oncol 2000;56:

11 32. Chadha M, Nanavati PJ, Liu P, et al. Patterns of failure in endometrial carcinoma stage IB grade 3 and IC patients treated with postoperative vaginal vault brachytherapy. Gynecol Oncol 1999;75: Weiss E, Hirnle P, Arnold-Bofinger H, et al. Adjuvant vaginal high-dose-rate afterloading alone in endometrial carcinoma: patterns of relapse and side effects following low-dose therapy. Gynecol Oncol 1998;71: Anderson JM, Stea B, Hallum AV, et al. High-dose-rate postoperative vaginal cuff irradiation alone for stage IB and IC endometrial cancer. Int J Radiat Oncol Biol Phys 2000;46: Dusenbery KE, Carson LF, Potish RA. Perioperative morbidity and mortality of gynecologic brachytherapy. Cancer 1991;67: Petereit DG, Pearcey R. Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: is there an optimal fractionation schedule? Int J Radiat Oncol Biol Phys 1999;43: Hueguenin P., Baumert B., et al. Curative radiotherapy in elderly patients with endometrial cancer. Patterns of relapse, toxicity and quality of life. Strahlenther Onkol 1999;175: Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85: Bye A, Trope C, Loge JH, et al. Health-related quality of life and occurrence of intestinal side effects after pelvic radiotherapy--evaluation of long-term effects of diagnosis and treatment. Acta Oncol 2000;39: Bye A, Ose T, Kaasa S. Quality of life during pelvic radiotherapy. Acta Obstet Gynecol Scand 1995;74: Klee M, Thranov I, Machin PD. The patients' perspective on physical symptoms after radiotherapy for cervical cancer. Gynecol Oncol 2000;76: Klee M, Thranov I, Machin D. Life after radiotherapy: the psychological and social effects experienced by women treated for advanced stages of cervical cancer. Gynecol Oncol 2000;76: Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) Int J Radiat Oncol Biol Phys 1995;31: Laird RJA. Modeling the drop-out mechanism in repeated-measures studies. J Am Statistical Assoc 1995;90:

12 3. Study objectives To determine if postoperative vaginal brachytherapy, as compared to external beam pelvic radiotherapy, provides 1. an equally low 5-year actuarial vaginal relapse rate 2. an equal 5-year overall survival rate 3. a reduction of treatment related morbidity 4. a better quality of life 5. equal risks of distant metastases and endometrial carcinoma related death 4. Study design In this open, multicenter trial, 400 patients with stage I or 2A endometrial adenocarcinoma who meet the inclusion criteria will be randomised (1:1) to one of the following arms: 1. postoperative external beam pelvic radiotherapy (control arm) 2. postoperative vaginal brachytherapy (experimental arm) The objective is to estimate the difference in vaginal relapse rate between the two study arms with sufficient precision. Primary study endpoints will be 5-year actuarial vaginal relapse rate (VRR), the overall locoregional failure rate, and overall survival. Secondary endpoints will be quality of life, treatment related morbidity, rates of pelvic relapse and distant metastases, and local control and survival after relapse. 5. Patient selection 5.1. Inclusion criteria To be eligible for this trial, patients will need to meet all of the following inclusion criteria: 1. Endometrial carcinoma, with one of the following combinations of postoperative FIGO stage and age: a. stage 1C grade 1 or 2 and age 60 or over b. stage 1B grade 3 and age 60 or over c. stage 2A, any age, grade 1 or 2 d. stage 2A, any age, grade 3 with < ½ myometrial invasion 2. Surgery consisted of a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) 3. Histologically proven adenocarcinoma; grade of differentiation determined according to the FIGO/AFIP criteria; depth of myometrial invasion documented 12

13 4. WHO-performance status 0-2 (Appendix C) 5. Written informed consent 6. Baseline quality of life questionnaire completed 5.2. Exclusion criteria The following criteria exclude the patient from enrolment in this trial: 1. One of the following combinations of FIGO stage and age: a. stage 2B, 3 or 4 b. stage 2A and grade 3 with 50% or greater myometrial invasion c. stage IA or IB grade 1 or 2 d. stage 1B grade 3 and age below 60 e. stage 1C grade 1 or 2 and age below 60 f. stage IC grade 3, any age 2. Histological subtypes papillary serous carcinoma or clear cell carcinoma 3. Routine staging lymphadenectomy 4. Interval between the operation and start of radiotherapy exceeding 8 weeks 5. History of any previous malignancy, except for basal cell carcinoma of the skin 6. Previous pelvic radiotherapy 7. Hormonal therapy or chemotherapy for this tumour 8. Prior diagnosis of Crohn s disease or ulcerative colitis 6. Staging and treatment 6.1. Staging Pre-operative and postoperative staging procedures: 1. Medical history, physical and pelvic examination 2. Endometrial biopsy and/or endometrial curettage 3. Blood count and chemistry tests 4. Chest radiography 5. Abdominal CT- or MRI-scan: optional After surgery and pathology, the FIGO stage should be assigned on the basis of the surgical and histological findings (Appendix B). 13

14 6.2 Surgery A midline incision should be employed. Upon entry in the peritoneal cavity, fluid samples are to be obtained for cytology, either by aspiration of free fluid, or by instilling and aspirating 100 cc of normal saline solution. This is followed by a thorough intra-abdominal exploration with palpation of the abdominal and pelvic organs and of the periaortic and pelvic lymph node areas. Biopsies should be taken of any suspicious areas. The uterus is then evaluated for any breach in the serosa, the distal ends of the fallopian tubes are ligated, and an extrafascial hysterectomy and bilateral salpingo oophorectomy (TAH BSO) are performed. Clinically suspicious pelvic and/or periaortic lymph nodes are to be removed, but routine pelvic or periaortic lymphadenectomy should not be done. 6.3 Radiotherapy External beam pelvic radiotherapy Target Volume: The clinical target volume (CTV) consists of the proximal 1/2 of the vagina, the previous site of the uterus, the parametrial tissues, the internal iliac lymph node region, and the caudal part of the common iliac lymph node chain (to 2 cm below the level of the promontory). The PTV consists of the CTV with a 1 cm margin. Positioning and verification: The choice of the supine or prone position is left to the treating physician. In the case of prone positioning, the use of a belly-board is recommended. The positioning of the patients during simulation and treatment should be reproduced with the aid of orthogonal laser beams. The positioning should be verified by electronic portal images or megavolt films at least once, at the beginning of treatment. Dose and fractionation: 46 Gy, 2 Gy per fraction, 5 times a week. Dose specification and homogeneity requirements should be according to the ICRU-50 recommendations. The treatment should preferably be started within 4-6 weeks after surgery, but no later than 8 weeks after surgery. Technique: A four-field box technique will be employed. Dose distributions should be computed at the central plane and at a plane through the vaginal vault. Treatment with a full bladder is advisable. 14

15 Vaginal brachytherapy Brachytherapy is to be delivered with a vaginal cylinder, with the reference isodose covering the proximal 1/2 of the vagina. Low-dose-rate (LDR) and high-dose-rate (HDR) dose schedules will be used, which deliver an equivalent of Gy to the surface of the vaginal mucosa: LDR 30 Gy, at a dose rate of cgy/hr, in one session of 2-3 days; MDR 28 Gy, at a dose rate of 100 cgy/hr, in one session of 28 hours; HDR 21 Gy, in 3 fractions of 7 Gy, each 1 week apart. The dose should be specified in a point at 5 mm distance from the surface of the cylinder, in the central plane (i.e. the plane perpendicular to the cylinder axis, bisecting the vaginal sources). Furthermore the dose at the vaginal top, i.e. the dose at 5 mm depth from the surface on the axis of the cylinder, should be computed. This dose should not vary more than minus 5% or plus 10% of the specified dose. The choice of the dose rate is left to the treating physician. Simulation radiographs are to be taken in the anterior and lateral directions. Dose distributions should be obtained, and the dose in the bladder and rectum reference points (according to ICRU-38 criteria) and at the vaginal mucosal surface should be documented. In order to prevent vaginal adhesions, fibrosis and stenosis the patients will be informed about these possible side effects, and will be encouraged to resume sexual intercourse soon after the completion of treatment, using local lubricants such as K-Y jelly, or otherwise to use Vaseline tampons or vaginal dilators regularly. 7. Pathology 7.1. Histopathologic evaluation The examination of the hysterectomy specimens by the regional pathologist will determine the eligibility of the patients for the study. A standardized evaluation of the specimens according to international criteria is important to obtain information on the pathologic prognostic factors. It should be documented at which parts of the uterus the samples are obtained. The following samples should be obtained in all cases: a representative sample of the deepest myometrial invasion at a plane perpendicular to the serosal surface; a transversal section through the lower uterine segment just proximal to the endocervix; a longitudinal section through the lower uterine segment and endocervix, sections through both cornuae; and representative sections of the tumour. 15

16 16 version: March 2003

17 Macroscopic evaluation should include: - size and aspect of the uterus and adnexa, status of the serosal surface - location of the tumour in the uterus - size of the tumour (maximal diameter and thickness) - invasion to < 50% or 50% of the myometrial width - minimal distance (in mm) between the tumour and the serosa at the point of the deepest myometrial invasion - width of the uninvolved myometrium - involvement of the lower uterine segment and of the endocervix - involvement of the cornuae and of the fallopian tubes Microscopic evaluation should include: - histologic classification according to the International Society of Gynecologic Pathologists (Appendix D) - histologic grade according to the FIGO 1988 criteria (Appendix D) - invasion to < 50% or 50% of the myometrial width - minimal distance (in mm) between the tumor and the serosa at the point of the deepest myometrial invasion - involvement of the mucosa in the cornuae - involvement of the lower uterine segment - involvement of the endocervical glands and/or the cervical stroma - presence or absence of vascular invasion 7.2. Central pathology review Pathology review will be conducted at the LUMC Pathology Department by V.T.H.B.M. Smit and H. Beerman (Dept of Pathology, MCRZ locatie Zuider, Rotterdam). In addition to the review of the histopathologic diagnosis and microscopic evaluation, the review will focus on the clinical significance and reproducibility of the three-tiered (FIGO) grading system as compared to a twotiered grading system as proposed by Lax et al (20). In earlier studies and at the PORTEC-1 review the prognostic significance and reproducibility of the intermediate grade (grade 2) were found to be poor. The prospective evaluation of the two-tiered system, which discriminates between favourable and poor prognostic groups, will establish its clinical significance and prognostic strength as compared to the traditional three-tiered system. Furthermore, the pattern of myometrial invasion will be classified (pushing border versus infiltrative pattern) which has shown to be an independent prognostic parameter in earlier studies. 17

18 After inclusion of a patient in the study, the regional pathologist will be contacted by one of the study pathologists and be requested to take a separate sample of the tumour for the study purposes and send this extra paraffin-embedded block, along with the histopathologic slides and a copy of the pathology report, for review. The slides will be returned within three months. The paraffin blocks will be saved in a dedicated tissue bank for future pathologic studies of new prognostic factors and factors predicting response to radiotherapy. For these purposes, immunohistochemical studies (e.g. cell adhesion molecules and MMP s) and/or molecular genetic studies such as LOH-studies or specific mutation analysis of certain genes will be done on the tumour samples. 8. Follow up At the completion of treatment, an end-of-treatment follow up visit after 2-4 weeks should be planned by the radiation oncologist to assess the acute toxicity. The End of Treatment Form (Form 6, Appendix H) should be filled in at this visit, and a Quality of Life Questionnaire with a prestamped return envelope should be handed out to the patient. After this, the Quality of life Questionnaires will be sent directly to the patients who have given permission to do so and have provided their address (see section 9). The patients will be evaluated during alternating follow-up visits to their gynaecologist and radiation oncologist. Patients will be assessed every 3 months for the first 3 years, every 6 months during the fourth and fifth years, and then annually up to 10 years. At each follow-up visit, a history is to be obtained with special emphasis on treatment related morbidity, and a physical and pelvic examination will be done. The patient s performance status and body weight should be recorded. A chest radiograph and blood count and chemistry tests will be obtained once a year, up to the 5 th year. Other procedures, such as vaginal smears or biopsies and CT- or MRI-scans are to be done only on indication. A checklist is provided in Appendix H. The Late Side Effects Form (Form 8) consists of a shortened listing of the specific EORTC/RTOG criteria for late radiation morbidity (Appendix E). These forms are to be placed in the patient charts and filled in by the radiation oncologist at each follow-up visit. A baseline Late Side Effects Form will be filled in at the initial visit before the initiation of radiotherapy to assess the postoperative (baseline) situation for comparison with the side effects recorded after the completion of radiotherapy. The follow-up information for the trial will be provided by the radiation oncologists; thus, the Follow-up and Late Side Effects Forms (Forms 7 and 8) are to be sent in twice a year for the first 3 years, and then annually. For this purpose, it is preferable that the patients are followed by the radiation oncologist from the fifth year onwards. 18

19 Adverse effects will be scored according to the EORTC/RTOG criteria (43). In the EORTC/RTOG scoring system, grade 0 means absence of radiation effects and grade 5 means the effects led to death. The severity of reaction is graded from 1 through 4. Grade 1 and 2 complications are defined as mild or moderate side effects, no or simple medical interventions needed. Grade 3 complications are disabling symptoms requiring medical intervention, surgery and/or hospitalisation, and grade 4 are severe disabling radiation complications such as ulceration, fistula formation or perforation requiring major surgery. In general, major toxicities are reported as grades 3, 4 and 5 taken together. The EORTC/RTOG acute and late radiation morbidity scoring schemes are listed in Appendix E. In the case of vaginal or pelvic relapse, histology should be obtained and screening for distant metastasis should be done. In the case of an isolated vaginal or pelvic relapse, treatment with curative intent should be initiated whenever possible. The Recurrence Form (Form 9) should be filled in and sent in, together with full details of the treatment. The patient remains in the trial follow-up in order to evaluate the efficacy of salvage treatment and survival after relapse in the two study groups. After treatment for locoregional relapse, an End of Treatment Form should again be completed and the Follow-up and Late Side Effects Form routine be resumed. If distant metastases are diagnosed, it is preferred to obtain histologic or cytologic evidence whenever feasible. The Recurrence Form is to be sent in with details of palliative treatment, and the patient should be followed until death. 9. Quality of life assessment For the evaluation of the quality of life the EORTC (European Organisation for Research and Treatment of Cancer) Core questionnaire (QLQ-C30 version 3.0) will be used (Appendix F). The EORTC QLQ-C30 is a multidimensional, cancer-specific quality of life questionnaire developed by the EORTC Study Group on Quality of Life (QOL) for repeated assessments within clinical trials. It is developed in a cross-cultural setting and has been found valid and reliable for quality of life assessments in various cancer populations, irrespective of the specific diagnosis (38). Optional modules developed for specific diagnostic groups or specific treatment modalities can supplement it. The QLQ-C30 contains five functional scales (physical, cognitive, emotional, social and role functioning), a global health status/quality of life scale, three symptom scales (pain, fatigue and nausea/vomiting), and six single items assessing additional symptoms (dyspnoea, insomnia, loss of appetite, constipation, diarrhoea) and perceived financial impact. For the majority of the QLQ-C30 items a 4-point Likert-type response scale is used. Exceptions are the items for the global quality of life scale (were a 7-point scale is used). All subscale and individual item responses are linearly converted to 0 to 100 scales. A higher score for a functional and global quality of life scales 19

20 represents a better level of functioning. For the symptom scales and items, a higher score reflects a higher level of symptoms and decreased quality of life. The EORTC Study Group on QOL has designed or is in the process of designing and validating specific modules for bladder cancer (BLS24 and BLM30), prostate cancer (PR25), head and neck cancer (H&N35) and ovarian cancer (OV28). However, there is no EORTC- or other diagnosisspecific module for endometrial cancer. To evaluate specific symptoms occurring after radiation therapy for endometrial cancer, we developed for this study a symptom module to be used in conjunction with the EORTC QLQ-C30 (Appendix F). It contains two specific EORTC symptom subscales from other modules (the subscale for bowel and bladder symptoms from PR25 and the subscale for sexual problems from OV28) with 4-point Likert-type response scales, in accordance with the design of the QLQ-C30. The use of these subscales as a specific symptom module for this study (to be used in conjunction with the QLQ-C30) was approved by the EORTC Study Group on QOL. During informed consent the patient will be asked by the radiation oncologist to participate in the quality of life part of the study, and will be asked for approval to send her name and address to the Data Center for the purpose of directly sending the subsequent QOL questionnaires. If the patient consents, the radiation oncologist hands over the baseline questionnaire and an address sheet with a pre-stamped return envelope. After receiving the baseline questionnaire and address sheet at the Data Center, the patient s information will be entered in the database for QOL and an automated notification of the timing of the following QOL questionnaires will be obtained. Before sending out QOL questionnaires to the patients, the local investigator will be contacted to verify the patient s vital status. If there is no response, a reminder will be sent after two weeks. If a hospital and/or local investigator and/or local ethical committee refuses to transmit these individual patient data to the Data Center (based on privacy arguments, although the patient s consent for this procedure is specifically asked), then the QOL questionnaire collection is left to the responsibility of the local investigator. The QOL questionnaires will be handed out by the radiation oncologist at baseline and at the endof-treatment visit 2-4 weeks after the completion of radiotherapy (as at that time the date of completion of therapy is not known at the Data Center). From then on, the QOL questionnaires will be sent directly to the patients at 6, 12, 18, 24, 36, 48 and 60 months from the date of diagnosis. 10. Registration and randomisation Patients who are eligible for the study should be referred to the radiation oncologist immediately after the operation. Preferably, the gynaecologist already mentions the trial and briefly explains its 20

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