Radiation dose escalation using intensity modulated radiation therapy for gross unresected node-positive endometrial cancer

Practical Radiation Oncology (2014) 4, 90–98

www.practicalradonc.org

Original Report

Radiation dose escalation using intensity modulated radiation therapy for gross unresected node-positive endometrial cancer Kanokpis Townamchai MD a , Philip D. Poorvu MD a , Antonio L. Damato PhD a , Rebecca DeMaria BA a , Larissa J. Lee MD a , Suzanne Berlin DO b , Colleen Feltmate MD c , Akila N. Viswanathan MD MPH a,⁎ a

Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts b Department of Medical Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts c Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute; Harvard Medical School, Boston, Massachusetts Received 28 March 2013; revised 30 May 2013; accepted 1 July 2013

Abstract Purpose: To determine rates of nodal control and survival in patients with endometrial cancer treated with intensity modulated radiation therapy (IMRT) with dose escalation to unresected nodal disease. Methods and Materials: Between November 2005 and April 2011, 22 endometrial-cancer patients received IMRT with dose escalation to gross nodal disease with curative intent. Twelve were treated for recurrent disease (RD) and 10 in the primary setting, of whom 5 had a hysterectomy. The boost area included pelvic nodes in 9 patients (41%), paraaortic nodes (PAN) in 6 (27%) and both pelvic and PAN in 7 (32%). The median gross nodal dose was 63 Gy (range, 55-65). Rates of local control, disease-free survival (DFS) and overall survival (OS) were determined using the Kaplan-Meier method. Results: Median follow-up time was 37.6 months (range, 10-88). Median nodal size was 2.25 cm (range, 1-6.9). The median time to first relapse after IMRT was 12 months (range, 6-49). Relapses occurred in 5/12 RD (42%), 1/5 hysterectomy (20%), and 5/5 inoperable cases. Nodal relapses occurred in-field in 3/12 RD and 1/5 hysterectomy patients. At 3 years, nodal control was 86%,

Presented at the Annual Meeting of the American Society for Radiation Oncology (ASTRO), Boston, MA, October 28-31, 2012. Sources of support: This work was supported by the Chua Family Fund. Conflicts of interest: None. ⁎ Corresponding author. Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Department of Radiation Oncology, 75 Francis St, ASB 1, L2, Boston, MA 02115. E-mail address: [email protected] (A.N. Viswanathan). 1879-8500/$ – see front matter © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2013.07.002

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DFS was 58% and OS was 68%. Three patients experienced grade 3 late hematologic toxicity (anemia). No late grade ≥ 3 gastrointestinal or genitourinary toxicity occurred. Conclusions: In endometrial cancer, the use of IMRT for dose escalation to gross nodal disease is feasible with acceptable rates of toxicity. Patients with nodal recurrence or unresectable nodal disease after a hysterectomy may benefit from radiation dose escalation. © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Introduction

Methods and materials

Radiation therapy (RT) plays an important role in the management of gynecologic malignancies, particularly for patients with locally advanced or recurrent disease. The presence of paraaortic (PAN) or pelvic lymph-node metastases at diagnosis or at the time of recurrence is a poor prognostic factor for survival in patients with cervical or endometrial cancer. Patients with locally advanced or recurrent disease with positive PAN or pelvic nodes require treatment of the gross nodal disease in addition to the primary tumor. 1 Surgical debulking is the standard of care but may not be feasible due to the proximity of normal structures, comorbidities, or patient preference. In patients with unresectable disease, doses of conventional anteroposterior-posteroanterior (AP-PA) or 4-field RT to lymph nodes, particularly the paraaortic chain, may be limited by dose to surrounding normal-tissue structures. Though dose escalation may reduce nodal failures in the pelvis, 2 attempts at increasing the RT dose to the PAN have been associated with excessive toxicity. 3 Advantages of intensity modulated radiation therapy (IMRT) include dose conformity to the target volume, which may allow dose escalation while sparing critical structures better than conventional RT. 4-6 Several studies of pelvis-only or extended field IMRT (EF-IMRT) for gynecologic malignancies have shown good clinical outcomes with reductions in bowel, bladder, and bone marrow dose. 7,8 These have been associated with decreased rates of gastrointestinal (GI), genitourinary (GU), and hematologic toxicities when compared with historic series using conventional RT. 9 Studies using positron emission tomography (PET) fusion with computed tomography (CT) for EF-IMRT with dose escalation to the PAN have shown the feasibility of such an approach with adequate coverage of the positive PAN and sparing of normal-tissue structures including the small intestine, stomach, liver, colon, kidney, and bone marrow. 10,11 However, the relationship of RT dose escalation with IMRT to nodal control and survival outcomes remains to be clarified. This study reports the clinical outcomes associated with the use of IMRT with dose escalation to positive unresected pelvic or paraaortic lymph nodes in endometrial cancer.

Patients The records of 22 patients with endometrial cancer treated with IMRT between November 2005 and April 2011 were reviewed with institutional review board approval. Patients included had primary or recurrent endometrial cancer with grossly positive PAN or pelvic lymph nodes on CT, MRI or PET-CT; had no distant metastasis and received treatment with curative intent. Lymph-node status was classified as positive when a node larger than 1 cm (in short axis) was identified on CT or MRI or had positive fluorodeoxyglucose uptake on PET scan.

Radiation treatment All patients underwent CT simulation with custom immobilization. The treatment area was designed based on stage and extent of disease. The IMRT plan consisted of 7-9 fields, using 6 MV photons. The beam numbers that resulted in the most optimal plan were selected. The gross tumor volume for the lymph node(s) (GTV-LN) was defined as gross tumor as seen on CT or PET-CT fusion. The clinical target volume (CTV) included the GTV plus the pelvic or paraaortic nodal chain as described in the Radiation Therapy Oncology Group (RTOG) consensus guidelines for CTV delineation for endometrial cancer. 12 The nodal clinical target volume in the pelvic-node area included external, internal, and common iliac nodes; presacral nodes were included for patients with any cervical involvement. The CTV for the PAN was contiguous with the pelvic-node area and encompassed the aorta and inferior vena cava with an additional margin to cover lateral recesses extending to the psoas muscles. The planning target volume was set as an expansion of 7 mm beyond the CTV to account for patient motion and inter-fraction setup variation. The small bowel, bladder, and rectum were contoured as the organs at risk in pelvic RT. The small bowel was delineated by individual loops after ingestion of oral contrast. The kidneys and liver were additionally contoured for patients whose PAN were included in the RT field. Normal-tissue dose limits

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were for spinal cord, a maximum dose less than 45 Gy; for kidney, volume receiving more than 20 Gy less than 30%; and for liver, volume receiving more than 30 Gy less than 30%. For the small bowel, the evaluation threshold was a volume receiving more than 55 Gy less than 5 cc; however, in individual cases this dose threshold may have been exceeded with physician approval. Details of the RT treatment for each patient are listed in Table 1. The median first course dose was 45 Gy in 25 fractions (range, 37.8-45), the median sequential boost dose was 18 Gy given in 10 fractions (range, 10-20 Gy), and the median total dose was 63 Gy (range, 55-65 Gy). One patient was treated with 30.6 Gy to the whole abdomen with IMRT in addition to the pelvic and paraaortic nodal radiation. Twenty-one of 22 patients received pelvic radiation with or without paraaortic radiation; 1 patient who had a prior course of pelvic radiation received paraaortic radiation only. Dose escalation resulted in a total dose to the target nodes of ≥ 55 Gy in all cases (Fig 1). Table 1 lists the small bowel dosevolume histogram results as obtained on the initial treatment plan and based on a toxicity analysis in which all bowel was re-contoured for research purposes. 13 IMRT was delivered for the entire course of RT for 17 patients. Four patients received conventional 3-dimensional conformal RT for the first course followed by IMRT for the nodal boost and 1 patient received conventional RT and IMRT during the first course followed by IMRT for the nodal boost. Brachytherapy was administered to 16 patients. Due to our proactive medical management paradigm, all patients treated to the paraaortic nodes receive prescriptions for antiemetics and H2-blockers or protonpump inhibitors at the time of simulation and are instructed to take each daily 30 minutes before radiation starting on the first day of treatment. For patients treated to either pelvis alone or pelvis and paraaortics, anti-diarrheal medication is initiated with the first report of loose stools (prior to diarrhea) during treatment. Patients are instructed to start a prophylactic half to 1 tablet of an anti-diarrheal medication daily, and in some instances are also advised to start a bulk-producing fiber product. All patients are instructed to apply a moisturizing skin cream daily starting from the first day of treatment. Those requiring treatment to the lower vaginal area are given a sitz bath with diluted salts for soaking after they develop any perineal erythema. In the event of desquamation, Xeroform gauze (Covidien, Mansfield, MA) is applied twice a day to the affected area. Details of chemotherapy type and sequencing are listed in Table 1.

Patient characteristics are shown in Table 1. Of the 22 total patients, 9 had Stage IIIC, 1 had Stage IVA, and 12 had recurrent disease (RD). Of the 10 primary endometrialcancer patients, 5 had unresectable disease due to extensive cervical involvement and 5 had residual nodal disease after hysterectomy. Fourteen patients (64%) had PET scans and all revealed positive PAN or pelvic nodes or both; 8 did not have a PET/CT at diagnosis. Thirteen patients had pathologically positive nodes on nodal biopsy, whereas 9 patients had CT/MRI or PET for diagnosis. Median nodal size was 2.25 cm (range, 1-6.9).

Follow-up

Patterns of failure

While receiving RT, patients were evaluated weekly by their radiation oncologist to assess treatment-related toxicity. Following completion of RT, patients were seen on an alternating basis by their radiation and gynecologic

The median follow-up time was 37.6 months (range, 10-88). The median time to first relapse after IMRT was 12 months (range, 6-49). Details of the relapse characteristics are outlined in Table 1. Six patients, 2 with RD and 4 with

oncologists at 3-month intervals. Imaging and blood chemistry were performed at the discretion of the treating oncologist. Data were abstracted from the medical record and collected in a computerized database. All patients received at least one CT or MRI for follow-up 2-9 months after treatment, with repeat imaging 3-6 months later to assess any remaining lesions. Mortality data were obtained from the clinical record or the Social Security Death Index. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Acute toxicities included those occurring from the date of initial treatment to 90 days after completion and late effects included any subsequent toxicity.

Statistical analysis Rates of nodal control, freedom from distant metastases (distant control), disease-free survival, and overall survival were generated using the Kaplan-Meier method. Nodal control was defined from time of diagnosis to first radiographic or pathologic evidence of recurrence or progression within the pelvic or paraaortic area. Distant control was defined from diagnosis to time of recurrence outside the PAN or pelvic nodes. Disease-free survival was defined as the interval from diagnosis of primary or recurrent disease to the date of first evidence of disease recurrence or progression or death from any cause. Patients without progression, recurrence, or death were censored at the last follow-up visit. Overall survival was defined as time from diagnosis to death from any cause. All analyses were performed using SPSS (version 18; IBM, Armonk, NY).

Results Patients

Practical Radiation Oncology: March-April 2014 Table 1

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Detailed treatment characteristics

Patient Year Age Original pathology No. (y)

Indication for Region IMRT

1

2006 62

30% MMI, G2 EAC

Recurrence

2

2007 93

Recurrence

3

2008 56

60% MMI, UPSC/CC, conc colon ca 20% MMI, G1 EAC

Recurrence

4

2008 58

b 10% MMI, G2 EAC

Recurrence

5

2008 49

8% MMI, G1 EAC

Recurrence

6

2008 51

20% MMI, G1 EAC

Recurrence

7

2009 67

10% MMI, G3 EAC

Recurrence

Vaginal cuff mass (2.3 × 1.9 × 1.6 cm) L ext iliac LN (2 × 1.8 cm) Vag cuff mass (2.2 × 2 cm) R internal iliac LN (3.2 × 2.9 cm) L iliac LN (1.7 × 2.7 cm) L PAN (2.2 × 2 cm renal hilum), L common iliac LN (2.1 cm) Retroperitoneal mass (6.9 × 4.5 × 6 cm)

8

2009 66

10% MMI, MMT

Recurrence

L iliac LN (4 × 3.3 cm)

9

2010 58

0% MMI, G1 EAC

Recurrence

10

2010 64

90% MMI, St IIIC1 UPSC

Recurrence

11

2011 52

50% MMI, G3 EAC

Recurrence

Vaginal cuff (2 cm); R common iliac LN (2.2 × 1.5 cm); L common iliac LN (3.7 × 1.5 cm), multiple B ext iliac and ing LN Aortocaval LN (1.8 × 1.8 cm) Preaortic LN (0.8 cm) PAN (N 8 cm)

12 13

2011 56 2009 67

Recurrence c Primary

14

2010 57

15

2010 62

30% MMI, G1 EAC 65% MMI, St IIIC2, G3 EAC 100% MMI, St IIIC2, squamous/EAC G3 70% MMI, St IIIC2, G1 EAC

16

2010 47

Primary

17

2011 71

90% MMI, St IIIC2, G3 EAC 25% MMI, St IIIC2, G3 EAC

18

2005 51

cSt IIIC2, G3 EAC

Inoperable d

19

2006 79

cSt IIIC1, G3 EAC

Inoperable d

20

2009 70

St IVA UPSC

Inoperable d

21

2011 48

cSt IIIC2, G3 EAC

Inoperable d

22

2011 74

cSt IIIC2, G3 EAC

Inoperable d

Primary Primary

L iliac LN (12 × 9 × 4 cm) R iliac LN (6 × 5 × 4 cm) Vag cuff mass (4.5 × 4.3 cm) L ext iliac LN (2.2 × 1.9 cm) R iliac (1 cm), R obturator (8 mm) L ext iliac LN (2.5 × 2.7 × 3.7 cm)

PAN/vertebral body (2 × 3 cm) Extensive pelvic and PAN (contiguous, fixed to renal vein) L retroperitoneal (2.7 × 2.0 cm) PAN (2.7 × 2.5 cm) SMA to common iliac continuous nodal mass; common iliac LN (3 cm); L int iliac (4 × 3.5 cm); obturator LN (2.3 × 1.5 cm); L ext iliac LN (2.2 × 1.9, 1.8 × 1.1 cm) PAN (1.2 × 0.9 cm)

Primary

confluent PAN extending above pancreas; R int iliac (1.2 × 1.1 cm); L int iliac (1.1 × 0.7 cm); R ext iliac (2.2 × 1.6 cm); L ext iliac LN (2.3 cm) Cervix (6 cm, uterosacral +); PAN (multiple, largest 2.5 × 1.8 cm; aortocaval 2.4 × 1.8 cm, R iliac 2.5 × 1.8 cm; L iliac 2.7 × 2.7 cm) Cervix/uterus (6.2 × 6 cm) R iliac LN (1.8 × 1.4 cm) L iliac LN (2.6 × 1.8 cm) Uterus/cervix (7.8 × 7.9 cm); Contiguous fixed PAN and pelvic LN, bladder involvement R common iliac LN (2.0 × 1.8 cm), R iliac LN (2.1 × 2.1 cm), L iliac LN (2 cm), matted PAN to renal vessels Cervix/uterus mass (5.3 × 2.9.2.7 cm); extensive PAN; L obturator LN (2.5 cm); L ext iliac LN (0.7 cm); R common iliac LN (1.7 cm)

(continued)

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Table 1 (continued) Patient Chemo type and RT sequencing No.

Dose (Gy) and Site: Small bowel Relapse sites 1st course and CD boost V55 Gy (cc) a (months from RT)

2

Conc Cis (75 mg/m 2) d 1 and 21 then Carbo/Taxol × 4 after RT None

3

Conc Bev (10 mg/m 2 × 3)

4

Conc Cis (50 mg/m 2 × 2)

5

None

6 7

Carbo/Taxol × 6 then conc Bev (10 mg/m 2 × 3) Conc Bev (10 mg/m 2 × 3)

8

Conc Cis (40 mg/m 2)

9

None

10

Recurrence after induction Carbo/Taxol 45 Gy Pelvis/PAN 18 Gy Pelvic LN; VB × 6 then conc Bev (10 mg/m 2 × 3) None 45 Gy Pelvis/PAN 20 Gy PAN None 45 Gy PAN 20 Gy PAN Carbo/Taxol × 4 then RT 45 Gy Pelvis/PAN 16.2 Gy Pelvis/PAN; VB Carbo/Taxol × 6 then RT 45 Gy Pelvis/PAN 10.8 Gy PAN; VB Carbo/Taxol × 3 then RT then 45 Gy Pelvis/PAN Carbo/Taxol × 3 19.8 Gy Pelvis/PAN; VB

1

11 12 13 14 15

41.4 Gy Pelvis/PAN b 22 Gy Pelvic LN; VB 45 Gy Pelvis b 20 Gy Pelvic LN 45 Gy Pelvis/PAN 16 Gy Pelvic LN 45 Gy Pelvis 18 Gy Pelvic LN; IB 45 Gy Pelvis b 20 Gy Pelvic LN; IB 45 Gy Pelvis/PAN 18 Gy PAN; VB 45 Gy Pelvis/PAN 18 Gy PAN 45 Gy Pelvis 18 Gy Pelvic LN 45 Gy Pelvis 18 Gy Pelvic LN; VB

45 Gy 18 Gy 45 Gy 18 Gy

Pelvis/PAN PAN; VB Pelvis/PAN Pelvis/PAN; VB

9.3 (22.3)

NED (85)

2.46

Central pelvis LN (48), DOC (48)

0.1

NED (61)

2.47

NED (55)

1.5 3

Pelvic and inguinal LN (45), DOD (45) NED (55)

4.6 (39)

NED (49)

2.3

NED (42)

7.1

DOC (20)

3.2

Lung metastasis (30), AWD (38)

6.1

3.9

Liver; peritoneal implants (4), AWD (28) PAN (5.7), DOD (10) L common iliac LN (15) (received 45 Gy), brain, DOD (24) NED (42)

16.7

NED (31)

3.2

NED (35)

8.8

NED (27)

3 5

16

Carbo/Taxol × 6 then RT

17

Carbo/Taxol × 4 then RT then Carbo/Taxol × 2

18

Conc Cis (40 mg/m 2 × 6)

37.8 Gy Pelvis/PAN b 18 Gy Pelvis/PAN; TB

0

Mediastinal LN (9), DOD (28)

19

Conc Carbo (AUC 1) × 5

0.3 (0.7)

Lung metastases (36), DOD (36)

20

Carbo/Taxol × 6 then RT

23.6

21

Conc Cis (40 mg/m 2 × 5)

PD in PAN (1); peritoneal carcinomatosis (3), DOD (50) PR (1); supraclav (2), DOD (12)

22

Conc Carbo (AUC 1) × 5

45 Gy Pelvis b 18 Gy Pelvic LN; TB 39.6 Gy Pelvis/PAN 23.4 Gy Pelvis/PAN; TB 45 Gy Pelvis/PAN 10 Gy Pelvis/PAN; TB 45 Gy Pelvis/PAN 12 Gy Pelvis/PAN; TB

4.7 (25) 7.1 (38)

Abdominal wall, L supraclavicular, axillary, inguinal LN (14), DOD (19)

B, bilateral; Bev, bevacizumab; Carbo, carboplatin; CD, cone down; cm, centimeter; Cis, cisplatin; conc, concurrent; cSt, clinical stage; DOC, died of other cause; EAC, endometrioid endometrial adenocarcinoma; ext, external iliac LN; G, grade; IB, interstitial brachytherapy; IMRT, intensity modulated radiation; LN, lymph node; MMI, myometrial invasion; MMT, carcinosarcoma; NED, no evidence of disease; PAN, paraaortic nodes; PD, persistent disease; PR, partial response; RT, radiation therapy; SMA, superior mesenteric artery; St, stage; TB, tandem-based brachytherapy; UPSC, uterine papillary serous carcinoma; Vag, vaginal; VB, vaginal cylinder brachytherapy. a Number in parentheses is based on re-contoured small bowel. b 4-field external beam first course. c Patient had prior pelvic radiation for vaginal cuff recurrence. d No hysterectomy feasible.

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Figure 1 Example of an axial (left) and sagittal (right) intensity modulated radiation therapy (IMRT) dose distribution for a patient treated with paraaortic and pelvic node extended-field IMRT.

unresectable disease, had distant-only relapse (1 mediastinal node, 2 lung, 1 liver and abdominal wall, 1 supraclavicular LN, and 1 abdominal wall and nodal progression). Distant metastasis was not associated with histology, time of treatment, chemotherapy, or extent of the RT field. Nodal relapses occurred in-field in 3/12 RD (in boost field) and 1/5 hysterectomy patients (not in boost field). For the nodal relapses after RT, the mean relapsed nodal size was 2 cm (range, 1.4-3.4).

Outcomes At 3 years, the actuarial rate of nodal control was 86%, the rate of distant control was 61%, disease-free survival was 58% and overall survival was 68% (Table 2; Figs 2 and 3). The 2-year rate of DFS was 68% and OS was 77%. For patients with recurrent disease, the 3-year nodal control rate was 91% (Fig 4) and the overall survival rate was 83%. No significant difference was observed in the rate of recurrence according to diagnosis of primary or recurrent disease, RT dose, or nodal size. In the entire cohort, patients with PAN involvement had a lower 3-year disease-free survival rate than patients who had pelvicnode involvement only (38% vs 87%, P = 0.03), but not overall survival (53% vs 89%, P = 0.37). Table 2 therapy

One patient had an acute grade 3 GI toxicity consisting of diarrhea requiring intravenous fluid support. She had received extended-field RT with boosts to both the PAN and pelvic nodes and also received chemotherapy. No acute grade 3 GU toxicity occurred. Grade 3 or grade 4 acute hematologic toxicity occurred in 7 patients treated with chemotherapy as follows: grade 3 neutropenia (4 patients); anemia (1); both (1); and grade 4 neutropenia plus anemia (1). Of these 7 patients, 4 had received RT to the pelvic nodes and PAN, 1 had received whole-abdominal RT, and 2 had received pelvic RT. No grade 3 GI or GU late toxicities occurred. Grade 3 late hematologic toxicity occurred in 3 patients (13.6%), all of whom developed anemia. There were no grade 4-5 late toxicities.

Discussion This study presents results of IMRT dose escalation to grossly positive pelvic and/or paraaortic lymph nodes in endometrial cancer. The administration of 55-65 Gy provided excellent clinical outcomes, including an 86% nodal control rate at 3 years and disease-free and overall

Three-year outcome for 22 patients treated with dose escalation to gross nodal disease using intensity modulated radiation

Variable

All patients Presentation Nodal site

Toxicity

n = 22 Primary (hysterectomy yes/no) (n = 10) Recurrence (n = 12) Paraaortic node involved (n = 13) Pelvic node only (n = 9)

Nodal control

Distant control

Disease-free survival

Overall survival

%

%

%

%

86 80/80 91 76 100

61 80/0 82 51 87

58 80/0 74 38 87

68 80/20 83 53 89

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Figure 2 Kaplan-Meier curve depicting disease-free survival for all 22 patients.

survival rates of 58% and 68%, respectively. Among all 22 patients, those treated with pelvic only gross nodal disease had excellent outcomes as did those presenting for treatment of recurrent disease. Those who were deemed inoperable and did not undergo a hysterectomy fared poorly. In contrast, only 3 of 12 patients treated for nodal relapses with IMRT had a nodal failure; additionally, 2 of 12 developed distant metastases but had achieved nodal control. Of 5 patients treated for gross residual nodal

Figure 3 Kaplan-Meier curve depicting overall survival for all 22 patients.

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Figure 4 Kaplan-Meier curve depicting nodal control within the radiation field.

disease after hysterectomy, only 1 developed a relapse, in an area that was not included in the boost field. No late grade 3 GI or GU toxicities were reported, which is lower than that expected with conventional RT. To date, only 1 other dose escalation study in patients with grossly positive nodal disease in endometrial cancer has been published to our knowledge, with significantly higher toxicity rates than in our series. 14 The reasons for the low toxicity rate in our series is unclear and may be due to differences in size of nodal disease, treatment planning constraints, total dose attempted, use of a sequential versus simultaneous boost, or other unknown factors. Studies of conventional RT with dose escalation in cervical cancer for the treatment of positive pelvic and paraaortic nodes have reported significant rates of toxicity. A study from the RTOG (RTOG 92-10) evaluated irradiation of positive PAN to 54-58 Gy using conventional RT with chemotherapy. Notably, the rates of bowel toxicity were unexpectedly elevated, with 24% of patients experiencing late grade 3-4 toxicity and one patient with grade 5 toxicity. 3 RTOG protocol 0116 delivered conventional RT to a dose of 54-59.4 Gy to the paraaortic or high common iliac lymph nodes with concurrent cisplatin with or without amifostine and, with a median follow-up time of 17 months, demonstrated a complete nodal response rate of 62%. The authors reported high rates of toxicity, with a higher than 80% rate of acute grade 3 or greater toxicity, and rates of late grade 3-4 toxicity up to 40%. Acute and late GI toxicity rates were approximately 30% and 20%. 15 In contrast, using IMRT, no grade 3-5 GI toxicities were noted using our initial planning dose constraint of less than 5 cc of small bowel to receive 55 Gy. We did not utilize a duodenal constraint and no duodenal toxicities were noted.

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For pelvic RT, previously reported rates of acute and late GI toxicity appear to be significantly lower with IMRT than with conventional treatment. Mundt et al 4,9,16 reported significantly lower rates of acute and late GI toxicity with pelvic IMRT compared with conventional RT (60% vs 91% and 3% vs 20% for acute and late toxicity, respectively). Kidd et al 17 reported that IMRT significantly reduced late grade 3 GI and GU toxicity from 16% with conventional RT to 7% with IMRT. A study from our institution 13 showed 6.5% late GI toxicity in patients with extended field IMRT and, of 12 patients who had dose escalation to 63 to 65 Gy, only 1 had GI toxicity. Though IMRT has been available for many years, its use for dose escalation of grossly involved nodal disease is evolving. Dosimetric studies of IMRT in gynecologic cancer have shown significant advantages relative to conventional techniques 18 allowing dose sparing of critical normal-tissue structures. 19,20 Studies have evaluated the feasibility of administering doses in the range of 59.4-60 Gy to positive PAN using IMRT. 11 Successful target volume coverage was achieved with acceptable dose to surrounding normal tissues. Limitations of this study include that it is a retrospective analysis of a series from a single institution. The low number of events prohibited multivariate analysis to identify risk factors for nodal failure. Most recurrences occur within the first 2 years; however, a few might be expected to occur after our analysis. As a retrospective series, heterogeneity in patient presentations and regimens limit generalizability. Despite these potential limitations, this study demonstrates the feasibility of obtaining excellent clinical outcomes with the use of IMRT for dose escalation in patients who either have had a hysterectomy and have residual gross nodal disease or have had a nodal recurrence of endometrial cancer. Patients deemed inoperable who did not have a hysterectomy were not able to be salvaged by radiation even with dose escalation. Furthermore, rates of GI toxicity were low, particularly compared with previous studies of conventional extended-field RT. Our study indicates that the benefits of dose escalation with IMRT are not outweighed by a significant additional risk of long-term toxicity. Whether IMRT with a higher level of dose escalation improves survival while maintaining low toxicity in patients with grossly enlarged nodes after surgery or with unresectable disease may be confirmed by future studies.

Conclusions The IMRT dose escalation technique enables the delivery of high-dose radiation to nodal regions in patients with endometrial cancer with gross residual nodal disease with low rates of acute and late high-grade

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toxicity relative to those expected with conventional RT. Investigation of further dose escalation above the median of 63 Gy used in this study may be warranted with careful assessment of surrounding normal tissues in patients with unresected nodes.

Acknowledgments The authors wish to thank Barbara Silver for reviewing this manuscript.

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