Radiation Therapy in Early Stage Endometrial Cancer: Update and Perspectives Arno J. Mundt MD Professor and Chair Department of Radiation Oncology

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1 Radiation Therapy in Early Stage Endometrial Cancer: Update and Perspectives Arno J. Mundt MD Professor and Chair Department of Radiation Oncology University of California San Diego

2 Radiation Therapy in Uterine Cancer Long history 1 st report published in 1909 Heyman (1935) reported a 58.2% 5-yr survival in early stage pts with the Stockholm Method (radium packing) Demonstrated curative potential of RT Heyman and Colleagues Radiumhemmet (1930s)

3 Historical Perspective Soon became commonplace, particularly pre-op By the 1980s, preoperative RT use declined Today, RT is almost exclusively delivered post-operatively in pts with adverse pathologic features Pelvic RT and/or vaginal brachytherapy (VB) Enthusiasm has waned for other previously popular approaches, e.g. whole abdominal RT (WART) and intra-peritoneal 32 P

4 When discussing preoperative RT, one needs to resurrect the old FIGO staging system Stage I IA IB Stage II Stage III Stage IV FIGO 1971 Clinical Staging System Corpus only Uterine cavity 8 cm Uterine cavity > 8 cm Corpus and cervix Extra-uterine disease (pelvis only) Extra-pelvic disease Rectal or bladder involvement FIGO =International Federation of Gynecology and Obstetrics

5 Preoperative RT Arguments Offered For Cytoreduction prior to surgery Spread of viable cells at surgery Better treatment tolerance Irradiation of well-oxygenated tumors Arguments Offered Against Over-treatment of low risk patients Loss of pathologic prognostic information* *most compelling argument (but overcome by operating within 2-3 days)

6 Preoperative RT Excellent pelvic control and survival in clinical stage I patients Pelvic 5-yr Year Control Survival Salazar % 82% Chung % 88% Bedwinek % 71% Weigensberg % 70-80%* Baram 1985 NS 72.4% Delmore % 84-91% Grigsby % 84% NS=not stated *5-yr DFS

7 Preoperative RT Serious complications are rare, particularly when brachytherapy is used alone Grigsby (1991) Retrospective review of 685 clinical stage I patients treated with preoperative RT Significant Treatment n GI toxicity ICB S % ICB + pelvic RT S % ICB S pelvic RT % ICB=intracavitary brachytherapy, S=surgery

8 Preoperative RT Greatest benefit in stage I g3 tumors Sause et al. (1990) Retrospective comparison of preop ICB versus surgery alone Grade 3/deep MI pts postop pelvic RT 5-year DFS All patients Grade 3 ICB S 94% 76% S 91% 53% Some institutions still recommend preoperative RT in clinical stage I g3 pts

9 Preoperative RT Stronger rationale exists in clinical stage II pts, particularly those with gross cervical involvement Analogous to bulky stage IB cervix pts

10 Preoperative RT 5-yr survivals in clinical stage II pts range from 70-80% Year 5-yr Survival Bruckman % Surwitt % Kinsella % (83% 5-yr DFS) Grigsby % Best outcomes in low grade tumors and those with microscopic cervical involvement Limited data in clinical stage III tumors

11 Preoperative RT What is the preferred preoperative RT approach? To answer this question, Wiegensberg (1984) performed a randomized trial Clinical Stage I Patients Regimen 1 ICB Hysterectomy Regimen 2 Pelvic RT Hysterectomy

12 Preoperative RT Preoperative ICB pts had Lower rate of residual disease Fewer pelvic failures Improved disease-free survival Fewer complications Residual Pelvic Disease Failure 5-yr DFS ICB S 50.9% 3.6% 80% Pelvic RT S 70% 12.6% 70% p =.02

13 Preoperative RT Technique ICB, pelvic RT or both Preferred approach in stage I disease is ICB alone Pelvic RT added in patients found to have deep MI and/or grade 3 disease In stage II pts, preoperative pelvic RT and ICB used

14 Preoperative RT Technique Heyman-Simon Capsules Traditionally low-dose-rate (LDR) techniques Fletcher-Suit combined with Heyman-Simon capsules mg-hr (vaginal apex Gy) If combined with pelvic RT, 2500 mg-hr intrauterine Some prescribe to Point A (à la cervical cancer) No recommendations for HDR brachytherapy

15 Is there a Future for Preoperative RT? Very limited at best At most centers today, only in clinical stage II pts with gross cervical involvement

16 Is preoperative superior to postoperative RT? To answer this question, the Gynecologic Oncology Group (GOG) launched GOG 16 Clinical Stage 1 Grade 1-3 Regimen 1 Preoperative RT Regimen 2 Postoperative RT However, it closed due to poor accrual Interest now turned to tailored postoperative RT

17 Postoperative RT

18 FIGO 1988 Surgical Staging System Early Stage Disease Stage I IA IB IC Stage II IIA IIB Corpus only Limited to the endometrium 1/2 myometrial invasion >1/2 myometrial invasion Corpus and cervix Endocervical glands only Cervical stromal invasion

19 Postoperative RT Early Stage Disease Very Contentious Issue All Patients Receive Adjuvant RT Even low grade minimally invasive tumors Center A No Patients Receive Adjuvant RT Even high grade Deeply invasive tumors Center B

20 Postoperative RT Early Stage Disease Controversy Exists Even When Given Pelvic RT Alone Pelvic RT + VB VB Alone Center A Center B Center C

21 Postoperative RT Rationale Early stage pts with adverse pathologic features are at risk for extra-uterine disease Most commonly cited pathologic factors: Myometrial invasion (MI) Tumor grade Cervical involvement Importance demonstrated in GOG 33

22 Surgical-pathologic study of 621 stage I pts Grade MI GOG 33 + Lymph Nodes Pelvic Paraortic 1 3% 2% 2 9% 5% 3 18% p< % p<.0007 None 1% 1% Superficial 5% 3% Middle 6% 1% Deep 25% p< % p<.0001 Creasman WT et al. Cancer 1987;60:2035

23 More useful to combine grade and MI +Pelvic Nodes Invasion G1 G2 G3 None 0% 3% 0% Inner 3% 5% 9% Middle 0% 9% 4% Deep 11% 19% 34% +Paraortic Nodes Invasion G1 G2 G3 None 0% 3% 0% Inner 1% 4% 4% Middle 5% 0% 0% Deep 6% 14% 23% Creasman WT et al. Cancer 1987;60:2035

24 Cervical involvement and CSI are also correlated with positive nodes + Lymph Nodes Pelvic Paraortic Site Fundus 8% 4% Isthmus-Cervix 16% p=.01 14% p=.0001 Capillary Space Involvement Negative 7% 4% Positive 27% p= % p=.0001 Creasman WT et al. Cancer 1987;60:2035

25 Rationale also provided by the correlation between adverse pathologic factors and vaginal failure Price (1965) 41 clinical stage I pts undergoing surgery alone Vaginal Recurrence All patients 14% Grade 1 4.4% 2 5.7% % MI None 3.7% <1/2 4.7% >1/2 15.1% Unfortunately, grade and MI not combined in the analysis Price et al. Am J Obstet Gynecol 1965;91:1060

26 Other Factors Other factors cited as risk factors for pelvic and/or vaginal failure: Tumor Size Schink (1991) Lower Uterine Segment (LUS) Mayr (1995) LUS is a common indication for adjuvant RT even without other high risk factors Schink et al. Cancer 1991;78:63 Mayr et al. Radiology 1995;196:323

27 Postoperative RT in Clinical Stage I Endometrial Cancer: Corpus, Cervical and Lower Uterine Segment Involvement- Patterns of Failure Mayr N et al. Radiology 1995;196:323 But. Only 4 patients with +LUS were treated with surgery alone 2/4 (50%) recurred And deep MI defined as >2/3 invasion Many or all four may have been stage IC

28 41 pathologic stage I pts All +LUS but negative cervical involvement Pelvic/Vaginal Recurrence -RT +RT Low Risk 0/25 0/2 ( 1/2 MI, g1-2) High Risk 3/6 1/8 (> ½ MI, g3) LUS involvement does not appear to be an independent risk factor for recurrence Phelan et al. Gynecol Oncol 2001:83:513

29 What evidence supports the use of adjuvant RT in stage I-II disease?

30 Numerous studies focused on postoperative RT in pathologic stage I-II pts Important differences exist Patients vary Some include only low risk tumors, others focus on high risk ones Surgical approaches vary Some include full surgical staging (pelvic and pelvic lymph node assessment) others do not RT approaches vary Some treat pts with pelvic RT, others focus on VB alone or pelvic RT + VB

31 Postoperative RT Stage I-II Disease Despite such differences, pelvic/vaginal control rates >95% in most reports Survival rates are also excellent Stage I 82-98% Stage II 68-93%

32 Selected Pathologic Stage I-II Postoperative RT Studies Recurrence 5-yr Author Stage RT Vagina Pelvis SV Alektiar IBg1-2 VB - 4% 94% Alektiar IB-IIB VB 2% 4% 93% Anderson IB-IC VB 0.9% 1.9% 84% Boz IAg3-IC P 4% 88% Calvin IIA-B P+/-VB,VB 2% 4% 85.2% Carey IBg3-II P+/-VB 3.9% 81% Chadha IBg3-IC VB 0% 81% Feltmate II P+/-VB,VB 3.7% 3.7% 93% Greven IA-IIB P+/-VB,VB 3.7% 0.7% 86% Nori I-II VB+/-P 2% 96.6% Rush IB-IC P 0% 0% 92% Weiss IC P 0% 1.6% 86%* Burke T, Muggia F, Mundt AJ. Uterine Cancer. In: Devita, Hellman, Rosenberg (eds). Principles and Practice of Oncology (2005)

33 Retrospective studies suggest a benefit to RT in pts with adverse pathologic factors Pelvic Recurrence +RT -RT Carey (1995) Hi risk pts 3.9%* 14.3% (deep MI, g3, +cervix) Pitson (2002) Stage II 5.6% 22.2% *includes non-irradiated patients Carey et al. Gynecol Oncol 1995;57:138 Pitson et al. Int J Radiat Oncol Biol Phys 2002;53:862

34 Retrospective review of 927 stage I-II patients Vaginal Recurrence +RT -RT Low risk stage I 0% 3.2% (g1-2, <1/3 MI) Hi risk stage I 1.1% 11.7% (g3, >1/3 MI) Stage II 0% 12.8% Elliott et al. Int J Gyne Cancer 1994:4:84

35 608 stage IA-IIA patients 22% pts with high risk features received adjuvant RT Multivariate analysis: adjuvant RT associated with DFS and Survival controlling for age, grade, stage, and surgical staging p-value HR 95% CI DFS OS Macdonald et al. Gynecol Oncol 2006;103:661

36 Postoperative RT Pathologic Stage I-II Disease Four prospective randomized clinical trials (RCT) have been performed evaluating postoperative RT in early stage patients Norwegian Trial PORTEC GOG-99 ASTEC/NCIC

37 Norwegian Trial Aalders (1980) Clinical Stage I N=540 TAH-BSO without lymph node sampling No assessment of peritoneal cytology Vaginal Brachytherapy 60 Gy vaginal surface Regimen 1 Pelvic RT 40 Gy (midline block after 20 Gy) Regimen 2 No further therapy Aalders et al. Obstet Gynecol 1980;56:419

38 Norwegian Trial Pelvic RT decreased vaginal/pelvic failures in pts with high risk features (deep MI, grade 3) tumors Vaginal/Pelvic Recurrence -Pelvic RT +Pelvic RT Grade 1-2 tumors 1/2 MI 4.0% 2.3% >1/2 MI 9.8% 9.4% Grade 3 tumors 1/2 MI 5.6% 2.1% >1/2 MI 19.6% 4.5% Aalders et al. Obstet Gynecol 1980;56:419

39 Norwegian Trial No overall benefit in survival with pelvic RT 5-yr Survival Pelvic RT 89% No Pelvic RT 91% Only in pts with deeply invasive g3 tumors Deaths from Cancer Pelvic RT 18.2% No Pelvic RT 27.5% Low risk pts had a higher rate of distant metastases leading to more cancer deaths! Aalders et al. Obstet Gynecol 1980;56:419

40 . PORTEC Trial Post Operative Radiation Therapy in Endometrial Carcinoma Creutzberg (2000) Select Stage I grade 1 >1/2 MI grade 2 any MI grade 3 <1/2 MI N=715 TAH-BSO without lymph node sampling No assessment of peritoneal cytology Regimen 1 Pelvic RT 46 Gy/ 2 Gy fractions No vaginal brachytherapy Regimen 2 No further therapy

41 PORTEC Trial Irradiated pts had a superior pelvic control 5-yr Pelvic Recurrence Pelvic RT 4% No Pelvic RT 14% p <.001 No benefit in overall survival Even after controlling for age, grade and MI 5-yr Survival Pelvic RT 81% No Pelvic RT 85% Creutzberg et al. Lancet 2000;355:1404

42 Locoregional Recurrence 14% 4% Creutzberg et al. Lancet 2000;355:1404

43 GOG 99 Trial Stage IB-II (occult) N=392 TAH-BSO with selective bilateral pelvic and para-aortic lymphadenectomy Assessment of peritoneal cytology Regimen 1 Pelvic RT 50.4 Gy/ 1.8 Gy fractions No vaginal brachytherapy Regimen 2 No further therapy Keys et al. Gynecol Oncol 2004;92:744

44 GOG 99 Trial Irradiated pts had a superior pelvic control 2-year Locoregional Recurrence Pelvic RT 3% No Pelvic RT 12% p <.01 RT pts had a non-significant improved survival 4-year Survival Pelvic RT 92% No Pelvic RT 86% p =.55

45 Survival Surgery +RT Surgery Keys et al. Gynecol Oncol 2004;92:744

46 Post-hoc analysis High Intermediate Risk (HIR) patients Age 70 with 1 of the following risk factors (grade 2-3, LVI, outer 1/3 MI) Age 50 with 2 factors Any age with all 3 factors Only 1/3 of treated patients A non-significant survival favoring RT Insufficient statistical power 4-year Survival Pelvic RT 88% No Pelvic RT 74% p = NS

47 ASTEC/NCIC Stage IA-IIA Intermediate/High Risk IA-IBg3, IC-IIA N= 905 TAH-BSO Assessment of peritoneal cytology and nodes not required If done, +cyto and +node patients included (1/3 of enrollment) Regimen 1 Pelvic RT Gy/ Gy fractions VB optional (54%) Regimen 2 Observation VB optional (52%) ASTEC/NCIC Committee Lancet 2009;373-46

48 Results No benefit to pelvic RT in terms of overall and cause-specific survival Significant reduction in local relapse as 1 st failure site 6.1% vs 3.2% Increase in lifethreatening acute (<1% vs 3%) and late (0% vs 1%) sequelae

49 What do these trials teach us?

50 Lesson 1 Adjuvant RT is associated with a significant and profound improvement in loco-regional control in early stage endometrial cancer, particularly in women with high risk features

51 Lesson 2 Adjuvant Pelvic RT is associated with increased toxicity, primarily related to the GI tract

52 Severe GI toxicity highest in GOG 99 Suggesting an increased risk in surgically staged patients PORTEC GOG-99 Severe GI Sequelae 3% (5-year, actuarial) 8% (2-year, crude) In GOG-99, 2 RT pts died from intestinal injury and 6 developed grade 3-4 SBO (compared to 1 non-rt pt)

53 Intensity Modulated RT Intensity modulated RT (IMRT) may decrease the risk of severe sequelae Dosimetric studies demonstrate significant sparing of small bowel, bladder and rectum Preliminary outcome studies have noted low toxicity rates and excellent pelvic control

54 Clinical Outcome Studies Adjuvant IMRT in Endometrial Cancer Pelvic Chronic n FU DFS Control Toxicity Knab m 84% 100% No G2 Beriwal m 84% 100% 3.3% 3 yr G2 Knab et al. Int J RadiatOncolBiolPhys 2004;60:303 Beriwal et al. Int J RadiatOncolBiolPhys 2006;102:195

55 What do the randomized trials not teach us?

56 Un-Answered Question 1 Does adjuvant RT Increase survival in early stage endometrial cancer patients?

57 Is Survival Increased? None of the trials found a significant benefit in survival with RT However, none were well-suited to answering this question

58 Limitation #1 Follow-up times are limited Longer follow-up of patients who recur may be necessary to assess impact on survival

59 Limitation #2 Only two trials contained surgery alone (control) arms All women in the Norwegian Trial received adjuvant VB Half the patients in ASTEC/NCIC received VB

60 Limitation #3 GOG 99 included many low risk patients (58% IB, 82% g1-2) PORTEC excluded high risk pts (Stage IC g3-ii) GOG 99 included patients least likely to benefit and PORTEC excluded those most likely to benefit

61 Meta-analysis of adjuvant RT in stage I endometrial cancer 4 randomized trials (3 published, 1 unpublished) 1770 patients Significant improvement in locoregional control Kong et al. Ann Oncol 2007

62 No improvement in survival seen in overall group Borderline survival advantage favoring RT Patients with 2 high risk factors (Grade 3, > ½ MI) Kong et al. Ann Oncol 2007

63 Review of SEER data 4010 stage IC g3-4 and stage II (all grades) 2306 pts (Surgery external beam +/- VB) 1704 pts (Surgery alone) Significant benefits in OS and CSS In stage IC g3-4, stage II g2, stage g3-4 Lee et al. JAMA 2006;295:389

64 Is Survival Increased? Far from an academic question Lack of a perceived survival benefit led some to withhold adjuvant RT, even in women with multiple high risk features Despite multiple randomized trials demonstrating a profound locoregional control benefit

65 Immediate versus Delayed RT Salvage rates may not be as high as those commonly quoted >70% results are typically quoted Most studies do not support this, even in isolated vaginal recurrences Survivals typically range around 40-50% Poorer outcomes in non-vaginal pelvic recurrences

66 Salvage RT Series Locally Recurrent Endometrial Cancer Local 5-yr Author n Control Survival Kuten (1989) 51 35% 18% Jereczek (2000) 73 48% 25% Curran (1988) 47 48% 31% Jhingran (2003) 91 75% 43% Hoekstra (1993) 26 84% 44% Sears (1994) 45 54% 44% Hart (1998) 26 65% 53% Wylie (2000) 58 65% 53% Lin (2005) 50 74% 53% Creutzberg ( 03) 35 77% 65%

67 Overall Survival is Poor Particularly in high grade tumor recurrences Lin et al. Int J Radiat Oncol Biol Phys 2005;63:500

68 And the risk of toxicity should not be ignored 22 isolated vaginal recurrences 18 EBRT+HDR, 4 HDR alone Median follow-up 32 month 18% grade 3-4 GI toxicity 50% grade 3 vaginal sequelae Petignat et al. Gynecol Oncol 2006;101:445

69 Recommendation Adjuvant RT should not be withheld in stage I-II patients due to a lack of a perceived survival benefit A more judicious approach is to properly select patients with high risk features If withheld, follow closely to detect recurrences quickly, hopefully when small and isolated to the vagina

70 Un-Answered Question 2 What is the optimal adjuvant RT approach in early stage patients?

71 Optimal Approach Much is made of the fact that many of the pelvic recurrences in the GOG 99 surgery arm were in the vaginal vault Prompted some investigators to recommend VB as the sole adjuvant therapy in early stage surgically staged patients

72 Optimal Approach However, while most pelvic failures were in the vagina, 28% were non-central (sidewall) Concerning since GOG 99 patients were surgically staged Most likely will be higher in patients with incomplete surgical staging Sidewall recurrences, even when small, are rarely salvaged Necessary doses associated with considerable toxicity risk even when IMRT is used

73 With adequate surgical staging, outcomes are excellent with VB alone Recurrences n Vagina Pelvis Solhjem 100 0% 0% Horowitz 164 1% 0.6% Chadha 38 0% 0% Fanning 22 0% 0% Hong % 0% Solhjem et al. Int J Radiat Oncol Biol Phys 2005;62:1379 Horowitz et al. Obstet Gynecol 2002;99:235 Chadha et al. Gynec Oncol 1999;75:103 Fanning et al. Obstet Gynecol 1996:87:1041 Hong et al. Am J Clin Oncol 1997;29:254

74 VB versus Pelvic RT Surgically Staged Patients Unanswered Questions Does surgical staging obviate the need for and benefit of pelvic RT in high risk patients? When is surgical staging adequate? Do the number of nodes matter? 5? 10? 15? Or more? Do where they are taken from matter?

75 A Phase III trial is needed comparing VB and pelvic RT in surgically staged patients Stage I-II patients TAH-BSO with bilateral pelvic and para-aortic lymphadenectomy Assessment of peritoneal cytology Regimen 1 Pelvic RT Regimen 2 Vaginal brachytherapy

76 Don t expect such a trial from the GOG An equivalency trial would require thousands of patients GOG 99 took 8 yrs to enroll <500 women PORTEC-2 trial is comparing VB and pelvic RT in early stage patients Unlike GOG, PORTEC-2 does not include surgical staging and will exclude truly high risk patients

77 So what to do with the individual patient?

78 Decision to irradiate (or not) rests on a careful assessment of the benefits and risks of treating (and of not treating) Likelihood of Cure/Toxicity With RT Likelihood of Salvage/Toxicity Without RT If delivered, select approach with the highest efficacy and lowest toxicity

79 Stage I Patients Limited*/No Lymph Node Surgery Grade 1 Grade 2 Grade 3 IA VB 2 IB -- 1 VB 2,3 VB 2,3 IC Pelvic 4,5 Pelvic 4,5 Pelvic 4,5 *<10 nodes, limited number of sites (arbitrary definition) 1 low risk of vaginal recurrence and nodal involvement 2 low risk of nodal involvement 3 Consider pelvic RT instead if +LVI and close to ½ MI 4 others favor Pelvic RT +VB particularly in g3, but pelvic RT alone associated with equivalent control and less toxicity 5 intensity modulated pelvic RT if possible

80 Pelvic RT and VB traditionally combined in pathologic stage I-II pts, notably stage IC Pelvic RT Pelvic+VB ICg1 24.9% 39.5% ICg2 29.9% 48.4% ICg3 27.4% 61.3% Small et al. Int J Radiat Oncol Biol Phys 2005;63:1502 But published data do not support the combined approach

81 256 stage I with deep MI on 7 studies Local Recurrence n Pelvic Pelvic+VB Eifel % Sause % Konski % Torissi % -- Piver 32 0% -- Rush 53 0% -- Weiss 61 0% -- Mean % 0.97% 1999;92:599

82 Complications also increased with combined approach Randall M et al. Intracavitary Cuff Boost after External Beam Irradiation In Early Endometrial Carcinoma Int J Radiat Oncol Biol Phys 1990;10:49 Rectal Bleeding/ Proctitis EBRT 3.8% EBRT+VB 18.6% p =.01 Lack of benefit and increased risk of toxicity strongly argue against the combined approach in high risk stage I disease

83 In surgically staged patients, VB alone is becoming the preferred adjuvant RT approach Stage I Patients Surgically Staged* Grade 1 Grade 2 Grade 3 IA VB 1 IB -- VB 1 VB 1 IC VB 2 VB 2 VB 2 *>10 nodes, multiple sites (arbitrary cutoff) 1 low risk of pelvic recurrence 2 consider pelvic RT if not extensive lymph node surgery

84 What about Stage II patients?

85 In stage II patients, base decisions on the extent of cervical involvement, myometrial invasion and surgical staging Stage II Patients Limited*/No Lymph Node Surgery Grade 1 Grade 2 Grade 3 IIA ½ MI VB 1 VB 1 VB 1 >½ MI Pelvic Pelvic Pelvic +/-VB +/-VB +/-VB IIB Pelvic+VB Pelvic+VB Pelvic+VB *<10 nodes, limited number of sites (arbitrary cutoff) 1 low risk of nodal involvement

86 VB may not be necessary in stage IIA pts undergoing pelvic RT Calvin DB, Connell PP, Rotmensch J, Mundt AJ Surgery and Postoperative RT in Stage II Endometrial Cancer AJCO 1999;22: pathologic Stage II patients 32 (73%) Stage IIA disease 18/32 stage IIA pts treated with pelvic RT alone None failed in the pelvis Median follow-up 40 months

87 As in stage I patients, one should favor VB alone in surgically staged stage II patients Stage II Patients Surgically Staged Patients* Grade 1 Grade 2 Grade 3 IIA ½ MI VB 1 VB 1 VB 1 >½ MI VB 2 VB 2 VB 2 IIB Pelvic+VB 3 Pelvic+VB 3 Pelvic+VB 3 *>15 nodes, multiple sites (arbitrary cutoff) 1 low risk of nodal involvement 2 favor pelvic RT if not extensive nodal surgery 3 only do VB alone reluctantly if extensive nodal surgery (note: pre-sacral lymph nodes are not routinely assessed!)

88 What about Chemotherapy? Imperial Beach

89 A strong rationale exists for chemotherapy in high risk early stage patients Creutzberg C et al. JCO 2004;22:1234

90 Previously, there was a push for replacing RT with chemotherapy GOG 156 Stage IB-IIB TAH-BSO Selective Pelvic & PA nodal dissection Regimen 1 Pelvic RT Regimen 2 Adriamycin Cisplatin However, it closed due to lack of accrual

91 The Europeans have completed such a trial 2006;95:266 Stage ICg3 Stage IIg3 >50% MI Stage III Regimen 1 Pelvic RT (45-50 Gy) Regimen 2 CDDP, Adriamycin, Cytoxan 5 cycles

92 2006;95:266 Median follow-up 95.5 months No difference in 5-year DFS or OS RT reduced local recurrence, chemotherapy reduced distant failure

93 Chemotherapy alone does not control local disease Pelvic failure-free survival with (1) and without (0) cervical involvement 43 high-risk patients Adjuvant chemotherapy alone 17 (40%) failed in the pelvis 3-year actuarial pelvic failure 46.5% Factors predictive of pelvic relapse: +cervix, stage I-II disease Int J Radiat Oncol Biol Phys 2001;50:1145

94 Chemotherapy Such results suggest that a more prudent approach would be to combine chemotherapy and RT Published trials, however, have reported mixed results

95 GOG 34 Morrow (1990) Clinical Stage I-II TAH BSO Surgical Staging 1 or more risk factors >1/2 MI Pelvic/PA nodes Cervical involvement Adnexal involvement Pelvic +/- Paraortic Irradiation No Vaginal Brachy Regimen 1 Doxorubicin 60 mg/m 2 N= 92 Regimen 2 No further therapy N=89 Morrow et al. Gynecol Oncol 1990;36:166

96 GOG 34 Chemotherapy did not improve outcome 3-yr Extra-Pelvic Survival Failure RT alone 75% 22.5% RT +Adriamycin 68% 16.3% p = NS p = NS Moreover, 12 (7%) of these surgically staged patients developed a SBO after pelvic +/- PART But maybe adriamycin alone is not enough

97 To test a more aggressive regimen, the RTOG launched RTOG ;103:155 Stage I-III TAH-BSO +/- Nodal Surgery Grade 2-3 >1/2 MI +Cervical Stroma Extra-uterine (pelvic only) disease +washings Pelvic RT 45 Gy +VB CDDP 50 mg/m 2 Days 1,28 Maintenance Chemo CDDP 50 mg/m 2 + Paclitaxel 175 mg/m 2

98 RTOG 9708 Unsurprisingly, acute toxicities were significant (predominantly hematologic) 29% grade 3-4 (concomitant phase) 83% grade 3-4 (chemotherapy phase) High rate of chronic toxicity also seen 41% grade 2, 16% grade 3, 5% grade 4

99 Loco-regional control was high (>95%), Extra-pelvic recurrences were common (4-yr distant metastases 19%) 2-yr DFS 83% Based on these results, a randomized trial was initiated (RTOG 9905) Unfortunately, closed due to poor accrual

100 Combined Modality Trials Several new combined modality trials are underway or in the planning stages PORTEC-3 comparing pelvic RT versus pelvic RT + chemotherapy in high risk pts New GOG trial (concept only) compares pelvic RT versus VB + chemotherapy in surgically staged patients

101 Conclusions RT continues to play an important role in early stage endometrial cancer Its optimal role is still evolving Attention turning to combined modality approaches in high risk patients following surgery Novel approaches, notably IMRT, should help improve the quality and delivery of RT in these women