Initial Clinical Experience with Intensity-Modulated Whole-Pelvis Radiation Therapy in Women with Gynecologic Malignancies

Gynecologic Oncology 82, 456 – 463 (2001) doi:10.1006/gyno.2001.6250, available online at http://www.idealibrary.com on

Initial Clinical Experience with Intensity-Modulated Whole-Pelvis Radiation Therapy in Women with Gynecologic Malignancies 1,2 Arno J. Mundt, M.D.,* ,3 John C. Roeske, Ph.D.,* Anthony E. Lujan, Ph.D.,* S. Diane Yamada, M.D.,† Steve E. Waggoner, M.D.,† Gini Fleming, M.D.,‡ and Jacob Rotmensch, M.D.* ,† *Department of Radiation and Cellular Oncology; †Department of Obstetrics and Gynecology, Section of Gynecologic Oncology; and ‡Department of Internal Medicine, Section of Hematology/Oncology, University of Chicago Hospitals, Chicago, Illinois 60637 Received December 6, 2000

Objective. Our goal in this article to describe our initial experience with intensity-modulated whole-pelvis radiation therapy (IM-WPRT) in gynecologic malignancies. Methods. Between February and August 2000, 15 women with cervical (9) or endometrial (6) cancer received IM-WPRT. All patients received a treatment planning computed tomography (CT) scan. On each scan, the target volume (upper vagina, parametrial tissues, presacral region, uterus, and regional lymph nodes) and normal tissues (small bowel, bladder, and rectum) were identified. Using commercially available software, an IM-WPRT plan was generated for each patient. The goal was to provide coverage of the target with the prescription dose (45 Gy) while minimizing the volume of small bowel, bladder, and rectum irradiated. Acute gastrointestinal (GI) and genitourinary (GU) toxic effects in these women were compared with those seen in 25 patients treated with conventional WPRT. Results. IM-WPRT plans provided excellent coverage of the target structures in all patients and were highly conformal, providing considerable sparing of the bladder, rectum, and small bowel. Treatment was well tolerated, with grade 0 –1 GI and GU toxicity in 46 and 93% of patients, respectively. IM-WPRT patients had a lower rate of grade 2 GI toxicity (53.4% vs 96%, P ⴝ 0.001) than those treated with conventional WPRT. Moreover, the percentage of women requiring no or only infrequent antidiarrheal medications was lower in the IM-WPRT group (73.3% vs 20%, P ⴝ 0.001). While grade 2 GU toxicity was also lower in the IM-WPRT patients (6.7% vs 16%), this difference did not reach statistical significance (P ⴝ 0.38). Conclusion. IM-WPRT provides excellent coverage of the target structures while sparing critical neighboring structures in gynecology patients. Treatment is well tolerated with less acute GI toxicity

than conventional WPRT. More patients and longer follow-up are needed to evaluate the full merits of this approach. © 2001 Academic Press

Key Words: cervical cancer; endometrial cancer; radiation therapy; intensity-modulated radiation therapy.

INTRODUCTION

1

Radiation therapy (RT) is commonly used in the treatment of patients with cervical and endometrial cancer. Patients typically receive whole-pelvis RT (WPRT) alone [1, 2] or in combination with intracavitary brachytherapy (ICB) [3, 4]. The purpose of WPRT is to treat the primary tumor (or tumor bed), surrounding parametrial tissues, upper vagina, and regional (pelvic) lymph nodes. However, irradiation of these sites results in the treatment of considerable portions of the small bowel and rectum. Unsurprisingly, gastrointestinal (GI) sequelae are among the most common acute and chronic side effects in these women [3, 5, 6]. While the overall frequency of severe sequelae including fistulas and small bowel obstruction (SBO) is low, patients may experience a variety of problems ranging from chronic diarrhea to malabsorption of vitamins, lactose, and bile acids [7]. WPRT also entails treatment of a significant portion of the bladder and may result in genitourinary (GU) sequelae as well [3]. Considerable attention has been focused on reducing the risk of such sequelae, particularly small bowel injury, in patients undergoing WPRT. Mechanical means to displace the small bowel from the pelvis during treatment have been described [8, 9]. However, such methods are often cumbersome (on both patient and staff) and may be difficult to reproduce. Surgical approaches to hold the small bowel in the upper abdomen out of the treatment field include absorbable meshes [10, 11], tissue expanders [12], and omentoplasty [13]. While feasible in women undergoing surgery, such approaches are not applicable to patients undergoing definitive or preoperative RT. Moreover, these approaches have a small but finite risk of small bowel injury [14].

Presented at the 32nd Annual Meeting of the Society of Gynecologic Oncologists, Nashville, Tennessee, March 3–7, 2001. 2 The research reported in this publication is supported by a grant from the Illinois Department of Public Health. Its contents are solely the responsibility of the authors and do not necessarily reflect the official views of the Illinois Department of Public Health. 3 To whom reprint requests should be addressed at the Department of Radiation and Cellular Oncology, University of Chicago Hospitals, MC 9006, 5758 South Maryland Avenue, Chicago, IL 60637. Fax: (773) 702-0610. E-mail: [email protected]. 0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

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One approach that has received little attention in gynecologic oncology is intensity-modulated RT (IMRT). Unlike conventional RT, IMRT uses treatment beams of varying intensity, resulting in better conformity of the high-dose region to the target volume, thereby minimizing the volume of normal tissues irradiated. IMRT planning has been shown to offer considerable promise in a variety of tumors including breast cancer [15–19], head and neck cancer [20 –30], prostate cancer [31– 38], mesothelioma [39], and colorectal carcinoma [40, 41]. In an earlier report [42], we compared intensity modulated WPRT (IM-WPRT) and conventional WPRT in 10 cervical and endometrial cancer patients. IMRT planning was shown to reduce the volume of small bowel receiving the prescription dose by a factor of 2. Moreover, the volume of rectum and bladder irradiated to high doses was also significantly reduced. Others have noted significant similar benefits using IMRT planning in locally advanced cervical cancer [43]. However, no data are available to date in gynecology patients treated with IMRT. Earlier this year, we implemented IM-WPRT in our clinic at the University of Chicago for women with cervical and endometrial cancer. The purpose of this report is to describe our initial experience using this novel treatment approach. METHODS From February 2000 to August 2000, 15 women with gynecologic malignancies were treated with IM-WPRT in the Department of Radiation and Cellular Oncology at the University of Chicago. IM-WPRT treatment planning was described in detail in our earlier report [42]. In short, a custom immobilization device (Alpha Cradle, Smithers Medical Products, Inc.) was fabricated encompassing the upper and lower body of each patient to minimize setup variability. A computed tomography (CT) scan was then obtained in the treatment position using our departmental scanner (PQ5000, Marconi Medical Systems, Cleveland, OH). The CT scans were obtained from the L-4 vertebral body to below the ischial tuberosities (80 images/patient). Oral, intravenous, and rectal contrasts were administered to aid in the delineation of the target and normal tissues. Vaginal markers were used to identify the location of the cervix. A target volume was contoured on individual axial CT slices [32]. This volume included all areas of gross and potentially microscopic disease and consisted of the upper half of the vagina, parametrial tissues, uterus (if present), and regional lymph nodes (common, internal and external iliacs). Since the lymph node chains could not be directly visualized, they were defined by encompassing the contrast-enhanced pelvic vasculature with a 2-cm margin. The presacral region was included to the bottom of the S-3 vertebral body to provide coverage of the presacral lymph nodes and the uterosacral ligament. To take into account organ motion and setup uncertainty, the target volume was expanded by 1 cm in three dimensions [44].

The rectum and bladder were also contoured in all patients. The peritoneal cavity (excluding the rectum and bladder) from the level of L4 –5 was used to define the small bowel region. Individual loops of small bowel were not contoured separately. IM-WPRT plans were generated using a commercial inverse treatment planning system (CORVUS Version 3.0, NOMOS Corp., Sewickley, PA). This planning system produces optimal intensity modulation profiles (Fig. 1) using a simulated annealing algorithm. The prescription dose is defined by the user along with all dose-volume contraints of the target and normal tissues. Based on our earlier analysis [42], we generated a nine-field, coplanar IMRT plan using 6-MV photons for each patient. Fields were equally spaced at 40° intervals. The prescription dose in all patients was 45 Gy. The cervical cancer patients treated with ICB received an additional 30 – 40 Gy to Point A delivered with low-dose-rate techniques. The endometrial cancer patients treated with ICB received 20 –25 Gy to the vaginal surface. All patients were treated using a Varian CL2100 CD accelerator (Varian Associates, Palo Alto, CA) equipped with an 80-leaf multileaf collimator (MLC). Treatment was delivered in the step-and-shot mode. The accuracy of setup was verified on the first day of treatment and weekly with orthogonal X-ray films to verify the location of the isocenter. These films were checked prior to treatment by the radiation oncologist (A.J.M.). Patients were monitored weekly during on-treatment visits for acute side effects. Toxicity was divided into gastrointestinal (GI) (frequent stools, diarrhea, proctitis) and genitourinary (GU) (frequent urination, dysuria). The worst toxic effects noted during treatment were graded on a 4-point scale: 0 (none), 1 (mild symptoms, no medications required), 2 (moderate symptoms, medications required), 3 (significant symptoms, treatment interruptions and/or hospitalization required). The frequency of medication usage was also noted. As a comparison, the acute toxic effects of the IM-WPRT were compared with those of a cohort of 25 consecutive gynecologic cancer patients treated with conventional WPRT at our institution prior to the initiation of IM-WPRT. Acute toxicity in these women was assessed prospectively during therapy and obtained from a review of the treatment charts. Conventional (four-field) WPRT plans were generated for each patient using our three-dimensional planning system (PlanUNC). All patients received 45 Gy. The incidence of acute GI and GU toxicity was compared in the two groups with the ␹ 2 test. RESULTS The patient and tumor characteristics of the women treated with IM-WPRT are summarized in Table 1. Median patient age was 56 (range, 35– 86). Most (60%) had cervical cancer, predominantly FIGO stage IB. While 10 underwent hysterectomy prior to RT, 2 received preoperative RT, and 3, RT alone. Four women received adjuvant chemotherapy (weekly cisplatin). ICB was delivered following IM-WPRT in 8 patients.

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FIG. 1. Intensity map of the anterior field in a patient treated with IM-WPRT. Dark areas signify regions of high intensity and light areas signify regions of low intensity. The central portion of this field consists of predominantly low-intensity areas, thereby reducing the dose delivered to the small bowel. Other fields will have their own unique intensity maps.

The IM-WPRT plans provided excellent coverage of the target volume in all 15 women. On average, 98.4% of the target received the prescription dose. The regions receiving below 45 Gy were predominantly on the periphery of the target volume. None of the target tissues received below 44 Gy. The mean and maximum target volume doses were 47.8 and 53.9 Gy, respectively. The volume and magnitude of all regions receiving above the prescription dose were small. The portions of the target receiving 110 and 115% of the prescription dose (49.5 and 51.7 Gy) were ⬍20 and ⬍1%, respectively, in all patients. None of these volumes were located along the posterior bladder and anterior rectal walls in patients in whom adjuvant ICB was planned. The IM-WPRT plans had a high degree of conformity. In the upper pelvis, the high-dose region conformed well to the laterally situated pelvic lymph nodes and posterior presacral region, thereby sparing the small bowel. In the lower pelvis, similar conformity minimized the volume of bladder and rectum irradiated. These results are illustrated in an example patient (Figs. 2 and 3). The percentage volumes of small bowel, bladder, and rectum receiving 45 Gy were all reduced using IM-WPRT compared with conventional WPRT (Fig. 4). Treatment was well tolerated resulting in no unplanned treatment interruptions. Grade 0, 1, and 2 GI toxicity (exclusively diarrhea) was noted in 5, 2, and 8 women, respectively. Grade 0, 1, and 2 GU toxicity (frequency and dysuria) was noted in 9, 5, and 1 patient, respectively. No patient developed grade 3 acute toxicity. Of note, 2 women with GU symptoms (1 grade 1, 1 grade 2) were diagnosed with urinary tract

infections on treatment and had resolution of their symptoms with the initiation of antibiotics. All acute toxic effects resolved rapidly following the completion of IM-WPRT. None of the patients who subsequently received ICB had their treatment postponed secondary to persistent acute symptoms. The patient and treatment characteristics of the IM-WPRT and conventional WPRT patients are compared in Table 2. No significant differences were seen in terms of most patient and treatment factors including patient age, disease stage, tumor histology, radiation dose, and percentage of patients treated with prior hysterectomy. The conventional WPRT group had a trend toward a higher percentage of cervical cancer patients and women treated with concomitant chemotherapy. However, the only significant difference between the two groups was a higher percentage of conventional WPRT patients treated with ICB. The incidence of acute GI toxicity in the IM-WPRT patients is compared with that of the women who received conventional WPRT in Fig. 5. Overall, IM-WPRT patients had a lower rate of grade 2 GI symptoms (53.4% vs 96%, P ⫽ 0.001). The required medication usage also differed in the two groups. The percentages of patients requiring none or only infrequent antidiarrheal medications in the IM-WPRT and conventional WPRT groups were 73.3 and 20%, respectively (P ⫽ 0.001). A comparison of acute GU toxicity in the two groups is shown in Fig. 6. Most patients in both groups had either no or only mild GU symptoms. While the incidence of grade 2 TABLE 1 Patient and Tumor Characteristics: IM-WPRT Patients Characteristic No. of patients Age, years Median Range Tumor site Cervix Endometrium Histology Squamous cell Adenocarcinoma Other Stage Cervix IA/IB/IIA Endometrium IB/IC IIB/IVA Vaginal recurrence Median WPRT dose, Gy ICB Hysterectomy None Prior to RT Following RT Concomitant chemotherapy

n 15 56 35–86 9 6 9 3 3

2/5/2 1/1 1/1 2 45 8 3 10 2 4

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FIG. 2. Axial CT slice through the upper pelvis in a patient undergoing IM-WPRT. Superimposed on this slice are the target volume (blue) and isodose lines (100%, white; 90%, magenta; 70%, yellow; 50%, light blue). Note that the 90 and 100% isodose lines conform to the shape of the target, sparing the small bowel.

GU toxicity was lower in the IM-WPRT group (6.7% vs 16%), this difference did not reach statistical significance (P ⫽ 0.38). All IM-WPRT patients with measurable disease achieved a complete response following completion of therapy. At a mean follow-up of 5.7 months, all patients are without disease recurrence or chronic toxicity.

DISCUSSION IMRT represents a major advancement in the field of radiation oncology. Compared with conventional RT, IMRT provides the means of better conforming the prescription dose to the target tissues, thereby reducing the volume of neighboring critical structures irradiated to high doses. Improved dose

FIG. 3. Axial CT slice through the lower pelvis in a patient undergoing IM-WPRT. Superimposed on this slice are the target volume (blue) and isodose lines (100%, white; 90%, magenta; 70%, yellow; 50%, light blue). Note that the 90 and 100% isodose lines conform to the shape of the target, sparing the bladder and rectum.

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FIG. 4. Percentage volume of the small bowel, bladder, and rectum receiving 45 Gy in an example patient planned using both conventional WPRT and IM-WPRT. Note that the volume of small bowel receiving 45 Gy is reduced by 50% using IM-WPRT.

conformity is achieved by varying the intensity of radiation across each treatment field. This is particularly appealing in the treatment of irregularly shaped targets in close proximity to critical normal structures. IMRT planning has been shown to hold considerable promise in a number of tumor sites including breast [15–19], head and neck [20 –30], and prostate [31–38]. However, little attention has been focused on its use in female genital tumors. This is surprising since the merit of highly conformal therapy minimizing the dose delivered to the small bowel in these patients was first recognized in the 1970s [45]. In our earlier report [42], we compared conventional and IMRT planning in 10

TABLE 2 Patient and Treatment Characteristics: IM-WPRT versus Conventional WPRT Patients Characteristic Median age, years Tumor site Cervix Endometrium FIGO stage I–II III, IV, recurrent Histology SCCA a Other Treatment sequence RT/preoperative RT Postoperative RT Chemotherapy Median WPRT dose, Gy ICB a

IM-WPRT

WPRT

FIG. 5. Comparison of acute GI toxicity in patients treated with IMWPRT versus the comparison group treated with conventional WPRT.

patients with gynecologic tumors undergoing WPRT. While both approaches provided excellent coverage of the target tissues, significant reductions in the volume of normal tissues irradiated to high doses were seen using IMRT. At the 45-Gy dose level, the average volume of small bowel irradiated was reduced by a factor of 2 (17.4% vs 33.8%, P ⫽ 0.0005). The average volumes of bladder and rectum irradiated were both reduced by 23% (P ⫽ 0.0002 and P ⫽ 0.0005, respectively) [42]. Recently, investigators at Washington University have noted similar benefits in the volumes of small bowel, rectum, and bladder irradiated in women with locally advanced cervical cancer undergoing WPRT and paraaortic RT [43]. Despite these dosimetric benefits, few data are available for patients treated with IMRT. To date, the largest published experience is in head and neck [20, 21, 23–25] and prostate [29] cancer. Our report represents the first clinical experience using IMRT in cervical and endometrial cancer. All our IM-WPRT plans were highly conformal, providing

P value

56

54

0.70

60% 40%

84% 16%

0.09

80% 20%

84% 16%

0.74

76% 24%

60% 40%

0.39

87% 13% 26% 45 Gy 56%

80% 20% 56% 45 Gy 84%

0.59 0.07 1.00 0.03

SCCA, squamous cell carcinoma; RT, radiation therapy; ICB, intracavitary brachytherapy.

FIG. 6. Comparison of acute GU toxicity in patients treated with IMWPRT versus the comparison group treated with conventional WPRT.

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excellent coverage of the target and sparing of the surrounding normal tissues. Conformity was obtained at a price, namely, target dose uniformity. All plans resulted in regions receiving below and above the prescription dose. However, these regions were small in volume and magnitude and were not located in clinically significant locations. We were especially careful to avoid high-dose regions along the bladder and rectal walls in patients who were scheduled to later undergo ICB. Treatment was well tolerated in our patients. Most experienced only mild acute toxicity and none required interruption of treatment. Moreover, the toxicity profile of the IM-WPRT patients compared favorably with that of the conventional WPRT group. The rate of grade 2 GI toxicity was lower in the IM-WPRT group and the frequency of medication (antidiarrheal) use was reduced. These results suggest that minimizing the volume of small bowel and rectum irradiated to high dose translates into less acute GI toxicity. While IM-WPRT patients experienced less frequent grade 2 GU toxicity, the difference did not reach statistical significance. This may have been due to the small number of patients and low rate of significant bladder toxicity in both groups. Our results are consistent with those of Zelefsky et al. [31] and Hancock et al. [38] using IMRT in prostate cancer patients. A potential criticism of this analysis is that the conventional WPRT patients were not a matched control group. Unsurprisingly, differences existed between the IM-WPRT and conventional WPRT groups in terms of several clinical and treatment factors. Nonetheless, we feel that our comparison of the two groups remains valid. Both groups were planned by a single radiation oncologist (A.J.M.), identical targets were contoured, and the same dose was prescribed. All of the conventional patients underwent three-dimensional conformal RT planning. Moreover, both groups represent consecutive patients treated in our clinic and thus not selected patients. Due to a higher percentage of cervical cancer patients in the conventional WPRT, more of these patients received concomitant chemotherapy. However, all received concomitant cisplatin. While cisplatin may result in significant nausea and emesis [46, 47], it rarely results in diarrhea, unlike regimens containing 5-fluorouracil [48]. Since diarrhea was the sole GI toxic effect in both groups, the higher rate of significant GI toxicity seen in the conventional group is thus unlikely to be due to the greater use of cisplatin in the IM-WPRT group. Finally, the imbalance in the use of ICB is also not a concern since ICB was delivered following pelvic RT and thus could not impact on the risk of acute toxicity in these women. Given the limited follow-up of our patients, no definitive statements can be made regarding the efficacy and chronic toxicity of IM-WPRT. All patients with measurable disease obtained a complete clinical response and acute symptoms resolved rapidly following therapy. Given recent data correlating the incidence and severity of acute and chronic sequelae in gynecology patients undergoing RT [49], we remain optimistic

that the risk of late sequelae in our patients will also be reduced. We are currently attempting to further optimize IM-WPRT in our gynecology patients. To reduce overall treatment time, we have recently begun using a seven-field IMRT plan whenever possible. We have found that this approach is associated with comparable target coverage and can be delivered in less time. Currently, the IM-WPRT treatment, on average, requires 18 min. We are also exploring the use of smaller margins around target structures to further reduce the volume of normal tissues irradiated. However, the use of smaller margins requires careful and accurate daily setup to avoid underdosage of the target tissues [50]. Magnetic resonance imaging (MRI) may also aid in the delineation of disease in the parametrial tissues and surrounding normal tissues. IM-WPRT was used here to deliver conventional doses in women undergoing WPRT. However, a potential application of IM-WPRT is to deliver higher doses in select cases. This is an appealing approach in cervical and endometrial cancer patients with known lymph node involvement. Such patients have a high rate of pelvic failure even following adjuvant RT [51, 52], particularly patients with gross nodal involvement [53]. We are currently evaluating IM-WPRT as a means of delivering conventional doses to the tumor and regional nodes and higher doses to select intrapelvic sites. IMRT techniques may also offer the ability to deliver high central doses in women with cervical cancer unable to undergo ICB [54]. CONCLUSION Our initial experience with IM-WPRT in cervical and endometrial cancer demonstrates that IM-WPRT is a feasible and promising approach in these women. IM-WPRT provides considerable sparing of the neighboring small bowel, bladder, and rectum without compromising coverage of the target volume. The frequency and severity of acute toxicity were low and compared favorably with those of patients undergoing conventional WPRT. However, more patients with longer follow-up are clearly needed to evaluate the full merits of this approach. REFERENCES 1. Weiss M, Connell PP, Rotmensch J, Waggoner S, Mundt AJ. External pelvic radiation therapy in stage IC endometrial carcinoma. Obstet Gynecol 1999;93:599 – 602. 2. Yeh SA, Wan Leung S, Wang CJ, Chen HC. Postoperative radiotherapy in early stage carcinoma of the uterine cervix: treatment results and prognostic factors. Gynecol Oncol 1999;72:10 –15. 3. Perez CA, Camel HM, Kuske RR, Kao MS, Galakatos A, Hederman MA, Powers WE. Radiation therapy alone in the treatment of carcinoma of the uterine cervix: a 20-year experience. Gynecol Oncol 1986;23:127– 40. 4. Horiot JC, Pigneux J, Pourquier H, Schraub S, Achille E, Keiling R, Combes P, Rozan R, Vrousos C, Daly N. Radiotherapy alone in carcinoma of the intact uterine cervix according to G. H. Fletcher guidelines: a French cooperative study of 1383 cases. Int J Radiat Oncol Biol Phys 1988;14: 605–11.

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