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Split-Field Helical Tomotherapy With or Without Chemotherapy for Definitive Treatment of Cervical Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 1, pp. 263–269, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter
doi:10.1016/j.ijrobp.2010.09.049
CLINICAL INVESTIGATION
Gynecologic Cancer
SPLIT-FIELD HELICAL TOMOTHERAPY WITH OR WITHOUT CHEMOTHERAPY FOR DEFINITIVE TREATMENT OF CERVICAL CANCER ALBERT J. CHANG, M.D., PH.D.,*k SUSAN RICHARDSON, PH.D.,* PERRY W. GRIGSBY, M.D., M.S.,*yzk xk AND JULIE K. SCHWARZ, M.D., PH.D.* *Department of Radiation Oncology, yDivision of Nuclear Medicine, Mallinckrodt Institute of Radiology, zAlvin J. Siteman Cancer Center, xDepartment of Cell Biology and Physiology, and kDivision of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO Objective: The objective of this study was to investigate the chronic toxicity, response to therapy, and survival outcomes of patients with cervical cancer treated with definitive pelvic irradiation delivered by helical tomotherapy (HT), with or without concurrent chemotherapy. Methods and Materials: There were 15 patients with a new diagnosis of cervical cancer evaluated in this study from April 2006 to February 2007. The clinical stages of their disease were Stage Ib1 in 3 patients, Ib2 in 3, IIa in 2, IIb in 4, IIIb in 2, and IVa in 1 patient. Fluorodeoxyglucose–positron emission tomography/computed tomography (FDGPET/CT) simulation was performed in all patients. All patients received pelvic irradiation delivered by HT and high-dose-rate (HDR) brachytherapy. Four patients also received para-aortic irradiation delivered by HT. Thirteen patients received concurrent chemotherapy. Patients were monitored for chronic toxicity using the Common Terminology Criteria for Adverse Events version 3.0 criteria. Results: The median age of the cohort was 51 years (range, 29-87 years), and the median follow-up for all patients alive at time of last follow-up was 35 months. The median overall radiation treatment time was 54 days. One patient developed a chronic Grade 3 GI complication. No other Grade 3 or 4 complications were observed. At last followup, 3 patients had developed a recurrence, with 1 patient dying of disease progression. The 3-year progression-free and cause-specific survival estimates for all patients were 80% and 93%, respectively. Conclusion: Intensity-modulated radiation therapy delivered with HTand HDR brachytherapy with or without chemotherapy for definitive treatment of cervical cancer is feasible, with acceptable levels of chronic toxicity. Ó 2012 Elsevier Inc. Cervix, Cancer, PET, IMRT, Tomotherapy.
ited data are available for IMRT treatment of gynecologic malignancies. Several dosimetric studies reported a decrease in volume of small bowel, bladder, and bone marrow irradiated in simulated IMRT treatment plans when compared with conventional two- or four-field treatment plans (7–9). Reductions in acute gastrointestinal (GI) and hematological toxicity have been demonstrated with IMRT in comparison with conventional four-field techniques for treatment of gynecologic malignancies (10, 11). A preliminary study demonstrated a reduction in late GI toxicity with pelvic IMRT (12). There has been only one prospective study that evaluated IMRT in patients with intact cervical cancer. That study included 135 patients who received pelvic IMRT delivered by a linear accelerator, and demonstrated a reduction in Grade 3 or greater bowel or
INTRODUCTION Concurrent chemoradiation is the standard of care for treatment of cervical cancer. Multiple trials have demonstrated improved survival along with decreased local and distant relapse rates with the addition of concurrent chemotherapy to radiotherapy (1–3). Increased acute hematological, gastrointestinal, and genitourinary side effects have also been observed with the addition of concurrent chemotherapy to radiotherapy (3–5). Limited data are available regarding the long-term side effects of concurrent chemoradiation. Late Grade 3 or 4 complications, including small bowel obstruction, fistula formation, proctitis, and hematopoetic suppression, occur at rates as high as 23% (6). Intensity-modulated radiation therapy (IMRT) has been increasingly used to reduce treatment-related toxicity. LimReprint requests to: Julie Schwarz, M.D., Ph.D., Washington University School of Medicine, Department of Radiation Oncology—Campus Box 8224, Mallinckrodt Institute of Radiology, St. Louis, MO 63110. Tel: (314) 362-8502; Fax: (314) 7479557; E-mail: [email protected] Conflict of interest: none.
Acknowledgment—This research was presented in poster form at the 2009 annual meeting of the American Society for Radiation Oncology (ASTRO). Received May 6, 2010, and in revised form Aug 2, 2010. Accepted for publication Sept 30, 2010. 263
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bladder complications with pelvic IMRT in comparison with the conventional two-field technique (13). Helical tomotherapy (HT) is a method of delivering IMRT that combines the function of a linear accelerator and a helical CT scanner into one unit (14, 15). Dosimetric studies have suggested improved organ-at-risk sparing for pelvic irradiation with HT in comparison to nonhelical IMRT (16, 17). There are limited studies demonstrating low rates of acute toxicity with pelvic irradiation by HT for treatment of prostate and rectal cancer (18, 19). Recently, Hsieh et al. reported treatment planning results and acute toxicities for 10 patients with cervical cancer treated with HT (20). In that study, HT was shown to be technically feasible, with acceptable short-term clinical outcomes and acute toxicities. The investigators also showed lower mean doses to the rectum, bladder, and intestines with the use of HT compared with conventional whole pelvis radiation treatment. The goal of the present study was to evaluate the long-term clinical outcomes and chronic toxicities for 15 patients treated with adaptive split-field HT for cervical cancer. METHODS AND MATERIALS Patients This study included 15 consecutive patients with newly diagnosed cervical cancer treated with radiation therapy with curative intent from April 2006 to February 2007 at the Mallinckrodt Institute of Radiology. Analysis of this prospective registry study was approved by the Washington University Human Research Protection Office. All patients underwent a complete pretreatment staging workup, including a history and physical examination, examination under anesthesia, cervical tumor biopsy, diagnostic abdominal and pelvic CT scan, and whole-body FDG-PET/CT. All patients had three gold seed fiducial markers placed within the cervix at the time of examination. Patients were staged using the International Federation of Gynecology and Obstetrics (FIGO) clinical staging criteria. A repeat PET/CT scan was performed 3 months after completing radiation treatment to evaluate response and any residual or progressive disease.
Simulation and treatment planning All patients were immobilized with a customized device (Alpha Cradle, Smithers Medical Products, North Canton, OH) to minimize daily setup variability. All patients underwent FDG-PET/CT simulation. Simulation scans were obtained from the level of T10 to mid-thigh. To minimize bladder activity, a Foley catheter was placed in the urinary bladder before receiving FDG. Patients received 20 mg furosemide intravenously approximately 20 min after FDG injection and received intravenous fluid administration (1,000–1,500 ml of 0.9% or 0.45% saline) during the study. All patients also underwent CT simulation on a Philips Brilliance CT Scanner (Philips Medical Systems, Cleveland, OH) with 3-mm slice thickness for localization and alignment. The FDG-PET/CT and CT simulation images were registered using point and anatomic matching (21). The metabolically active primary cervical tumor and involved lymph nodes were contoured with FDG-PET/CT guidance. The FDG-avid, metabolically active primary cervical tumor (MTVCERVIX) was defined as the 40% threshold volume(22). The common iliac vessels (e.g., nodal regions) were contoured from the bifurcation of the aorta, inferiorly
Fig. 1. Positron emission tomography (PET) fusion and intensitymodulated radiation therapy (IMRT) contours. (A) Fusion image of fluorodeoxyglucose–positron emission tomography (FDG-PET) and planning CT scan showing the FDG-avid lymph nodes and nodal clinical target volume (CTVNODAL) contour in a coronal view. (B) Axial view of CTVNODAL, MTVCERVIX, and FDG-avid lymph nodes. (C) Contours for CTVNODAL and MTVCERVIX in a three-dimensionally rendered coronal view.
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Table 1. Treatment planning parameters Structure Bladder Rectum Bowel Pelvic bones Femoral heads
Volume (%)
Dose guideline (Gy)
Maximum dose (Gy)
20 40 60 20 40 60 20 40 60 20 40 60 20
45 40 30 45 40 30 45 40 30 45 30 20 45
54
40 60
30 20
54 54 54 54
to the level of the medial circumflex artery, including the external and internal iliac vessels. These contours were expanded 7 mm, followed by subtraction of the pelvic bones, femoral heads, and vertebral bodies to create the clinical nodal target volume (CTVNODAL). A 7-mm margin was added uniformly to CTVNODAL to create the final planning target volume (PTVFINAL). Four patients received para-aortic irradiation, in 3 cases prophylactically and in 1 case for para-aortic nodal involvement noted on pretreatment FDGPET/CT. For patients receiving para-aortic irradiation, the upper border of CTVNODAL included the para-aortic lymph nodes and normal vessels with the contour originating from the aorta and vena cava at the level of the renal vessels and extending to the bifurcation of the aorta or top of the pelvic lymph node volume. Figure 1 shows representative contours for MTVCERVIX and CTVNODAL. Normal structures contoured included the following: bladder, rectum (up to sigmoid colon), spinal cord, right and left femoral heads, pelvic bones (consisting of sacrum, coccyx, ilium, ischium, pubic rami, and acetabulum). The ‘‘bowel’’ (a bag-like structure including the small and large intestines) was constructed by contouring the outermost extent of the bowel loops and the free space in-between the loops. This offers some allowance of bowel mobility (23). Treatment planning was performed using the TomoTherapy HIART System (version 2.2.1, TomoTherapy, Inc, Madison, WI). Plans were subject to the constraint of delivering 100% of the prescription dose to 95% of the planning target volume (PTV). Plans were optimized to minimize normal tissue dose to the bowel, rectum, bladder, pelvic bones, and femoral heads (Table 1). The prescription for PTVFINAL was 50.4 Gy in 1.8-Gy fractions and 20 Gy to the MTVCERVIX. For patients receiving para-aortic irradiation, the dose to the para-aortic nodes was 45 Gy for prophylaxis and 50 Gy for para-aortic nodal involvement. Figure 1 illustrates several contoured structures, along with the 95% isodose line generated for 1 patient using the above treatment planning parameters. Figure 2 shows an example tomotherapy dose distribution with isocontours from the 50-Gy and greater line (left) and the 20 Gy and greater line (right). The dose–volume histogram for this patient is shown in Fig. 3.
Patient treatment Patients were treated on TomoTherapy HI-ART Systems with daily megavoltage (MV) CT localization. Patients were set up to
Fig. 2. Dose distribution for a typical patient. The dose distributions illustrate our planning objectives to treat the lymphatics (PTV) to 50 Gy (left) and the MTV cervix to 20 Gy (right).
bony landmarks such as the spinal column and pelvic bones. After the daily image fusion, any patient requiring a greater than 2.0-cm shift in any direction underwent reimaging. All MVCT images were reviewed by the treating physician on a daily basis. Four times a week, ‘‘short’’ MVCT images were taken through the target and were approximately 10 cm in length (superior to inferior). Once a week, the patient had a ‘‘long’’ scan that covered all irradiated volumes and was approximately 20 cm in length. The short scans are adequate for aligning the patient to the isocenter and require less acquisition time. The long scans are useful for observing anatomical changes through the treated volume.
Chemotherapy and intracavitary brachytherapy Thirteen of 15 patients received concurrent chemoradiation therapy. Concurrent chemotherapy consisted of single-agent weekly cisplatin at 40 mg/m2 in 11 patients, weekly cisplatin 40 mg/m2, and infusional 5-fluorouracil 2 to 5 mg/m2 in 1 patient, and weekly
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histology. The median tumor size was 5 cm. In 5 of the 15 patients, the pelvic nodes were positive on pretreatment FDG PET/CT. Para-aortic lymph node involvement was noted in 1 patient. Of the patients, 73% completed all of their planned radiation treatments. Two patients did not complete radiotherapy for reasons unrelated to radiotherapy. One patient developed a brain metastasis during treatment and decided to not proceed with pelvic radiotherapy. One patient was hospitalized for sepsis and self-discontinued her treatment.
Fig. 3. Dose–volume historgram for the same patient as in Fig. 2. The planning target volume (PTV) is shown in blue, and the MTV is shown in red. carboplatin in 1 patient. Of the 13 patients receiving concurrent chemoradiation, 12 patients completed all planned chemotherapy cycles without any dose reduction. All patients received highdose-rate (HDR) brachytherapy delivered in six weekly fractions of approximately 6.5 Gy to Point A using an Iridium-192 source and Fletcher-Suit-Declos CT/MR compatible titanium intracavitary applicators (Varian Medical Systems, Palo Alto, CA). Patient treatment plans were developed on either 3D MRI or CT images. The 2-cc bladder and rectum doses were monitored according to the European Society for Therapeutic Radiology and Oncology guidelines (24). All patients were weighed before brachytherapy treatment. The median overall treatment time was 54 days. No treatment breaks were required.
Survival/recurrence The median follow-up for all patients was 35 months (range, 27–42 months). The 3-year cause-specific and progression-free survival estimates were 93% and 80%, respectively (Fig. 4). At the time of last follow-up, 9 patients were alive with no evidence of disease, whereas 3 patients had died of causes unrelated to their cancer. Three patients (20%) developed recurrences, two of which were distant only, and one of which was both local and distant. The single local failure occurred in a patient who presented with synchronous anal and cervical squamous cell cancers. She was prescribed 54 Gy to the anal tumor with 20 Gy to the MTV cervix and 50.4 Gy to the pelvic, paraortic, and inguinal lymph nodes. She also
Table 2. Patient characteristics and pathologic factors (N = 15) Characteristic
Toxicity assessment Follow-up examinations were performed approximately every 2 months for the first 6 months, every 3 months for the subsequent 2 years, and then every 6 months thereafter. Patients were evaluated for disease status and for the appearance of toxicity, with history and complete physical examinations in addition to laboratory and radiological tests. In most patients, FDG-PET was performed 3 months after completion of treatment and then yearly or when warranted by clinical examination or symptoms. Late complications were reported as events occurring after 90 days after completion of therapy. Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 was used to score the maximum late toxicity (http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf).
Statistical analysis Survival, tumor recurrence, and actuarial complication rates were measured from the completion of treatment. StatView Version 5.0.1 software (SAS Institute, Cary, NC) was used for the analysis. The Kaplan–Meier (product–limit) method was used to derive estimates of survival based on total sample size (25).
RESULTS Patient characteristics Fifteen consecutive patients with cervical cancer were treated definitively with curative intent using HT. The baseline characteristics of the entire cohort of patients are summarized in Table 2. Of the tumors, 86% were of squamous
Age, y, median (range) Follow-up, mo, median Stage (n; % of total) IB1 IB2 IIA IIB IIIA IIIB IVA Tumor diameter, cm, mean (range) #2 cm >2 cm to #4 cm $4 cm Not determined Pelvic lymph node involvement Positive Negative Para-aortic lymph node involvement Positive Negative Grade (n; % of total) 1 2 3 Undetermined Histology Squamous Adenocarcinoma Clear cell
Result 51 (29–87) 34 3 3 2 4 0 2 1 5 (2.23–6.46) 1 3 10 1
(20%) (20) (13) (27) (0) (13) (7) (7%) (21) (71)
5 10 1 14 2 9 3 1
(13%) (60) (20) (7)
13 1 1
(86%) (7) (7)
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Table 3. Late/chronic toxicities potentially related to chemoradiation therapy according to CTCAE v3.0 criteria Grade Toxicity
I
II
III
IV
V
Gastrointestinal Genitourinary Fracture Pain
3 0 0 2
2 2 0 0
1 0 0 0
0 0 0 0
0 0 0 0
para-aortic plus pelvic irradiation with concurrent weekly cisplatin. No other chronic Grade 3 toxicities were noted.
DISCUSSION
Fig. 4. Kaplan–Meier curves for (a) progression-free survival and (b) cause-specific survival.
underwent HDR brachytherapy for an additional 39-Gy boost to the cervical tumor. This patient experienced recurrence locally in two lymph nodes, one perirectal and one inguinal. These were detected radiographically, along with distant failures in the mediastinal and supraclavicular regions, 1 year after the completion of treatment. The inguinal lymph node was included in the 50.4-Gy PTV; the perirectal lymph node, which was not positive on pretreatment imaging, was located within the 30 Gy isodose line for the IMRT plan. This patient died 8 months later of disease progression. Toxicity Detailed chronic toxicities for the entire patient population (N = 15) are presented in Table 3. The majority of late toxicities were Grade 1 (33.3%) and Grade 2 (26.7%). There were 3 patients with chronic Grade 1 GI toxicities (1 constipation, 1 proctitis, 1 bleeding with no intervention necessary) and 2 patients with chronic Grade 1 pain. Four patients experienced chronic Grade 2 toxicities (1 rectal bleeding requiring minimal cauterization, 1 anorectovaginal fistula, and 2 cystitis). The patient with the Grade 2 anorectovaginal fistula also presented with a concomitant squamous cell carcinoma of the anus in addition to cervical cancer. One Grade 3 late effect (6.7%) was observed. This patient sustained a small bowel obstruction after receiving
In this study, we demonstrate that HT is a feasible method of IMRT delivery for definitive treatment of patients with intact cervical cancer. The local control rate at 36 months was 93%, with only one local failure among 15 patients. The median overall treatment time was 54 days, with no patients requiring a treatment break. When concurrent chemotherapy was administered in our study, 92% of patients completed all planned chemotherapy. Although this study was not designed for direct comparison with the conventional four-field technique, the rate of completion of chemotherapy is higher than the 49% rate of completion observed in patients receiving weekly cisplatin chemotherapy with two- or four-field conventional radiotherapy (2). The maximal benefit of combined radiation and chemotherapy may be realized with HT through minimization of radiation treatment breaks and alterations in the planned chemotherapy schedule. A preliminary study demonstrated that IMRT for treatment of gynecological malignancies reduced chronic GI toxicity when compared with conventional technique (12). This study had limited follow-up and included a heterogenous cohort of patients diagnosed with endometrial and cervical cancer, with some of the patients undergoing surgery. A recent publication from our institution demonstrated that nonhelical IMRT for intact cervical cancer reduced the rate of Grade 3 or greater bowel and bladder complications according to CTCAE v3.0 criteria when compared with the conventional two-field technique (6% vs. 17%) (13). Our rates of chronic toxicity in this current study are consistent with those published by Kidd et al., with only 1 patient (7%) experiencing a Grade 3 complication based on CTCAE v3.0 criteria. This patient received para-aortic plus pelvic radiation with concurrent cisplatin chemotherapy, which likely contributed to the toxicity. Concerns about target motion and deformation resulting in a geographic miss have limited the widespread use of IMRT for gynecologic cancer. A study demonstrating significant interfractional cervical tumor motion suggested a generous PTV margin to account for the target motion (26, 27), which can increase the volume of normal tissue irradiated and decrease the benefit of IMRT (28). However,
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Van de Bunt et al. found that IMRT is superior in the sparing of critical organs to conventional or conformal radiotherapy, even with bladder motion, rectal motion, and tumor regression considered (29). The advantage of using HT in our study was the ability for daily MVCT image registration with the treatment planning CT. Although all patients are set up based on bony landmarks, in our study, all patients received gold seed fiducial markers placed in the proximity of the cervical tumor (see Methods and Materials). This allowed us to monitor daily target motion on MVCT scans, and ensured consistency of patient setup and adequate CTV coverage. In addition, the treatment planning isodose line projection onto the MVCT scan allowed monitoring of any organs at risk (such as small bowel) that could dip into the highdose regions. Patient weight was also carefully monitored for any significant weight gain or loss. Although no patients in this study required it, in our clinic adaptive planning has been done for patients who had a significant weight change.With daily image guidance, a 5-mm PTV margin expansion has been suggested to be sufficient (30). In our study, we used a 7-mm PTV margin expansion.
Volume 82, Number 1, 2012
Our study is limited by a retrospective analysis of patient outcomes and a small patient population. To limit selection bias, we evaluated 15 consecutive patients with intact cervical cancer who were treated with HT, which resulted in an even distribution of patients ranging from Stage Ib1 to Stage IVa. Although our study reports the longest follow-up for HT in gynecologic cancer to date, it should be noted that Grade 3 or greater rectal and urinary complications can occur up to 25 years after treatment. Given that the majority of chronic complications from radiation therapy for gynecologic cancer occur within the first 3 years after the completion of therapy (31), it is likely that the majority of complications resulting from treatment have been accounted for within our followup period. CONCLUSION This study shows the feasibility of treatment of intact cervical cancer with split-field IMRT using HT, with low rates of chronic toxicity while maintaining excellent disease control.
REFERENCES 1. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137–1143. 2. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153. 3. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–1161. 4. Tseng CJ, Chang CT, Lai CH, et al. A randomized trial of concurrent chemoradiotherapy versus radiotherapy in advanced carcinoma of the uterine cervix. Gynecol Oncol 1997;66:52– 58. 5. Peters WA, 3rd, Liu PY, Barrett RJ, 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606–1613. 6. Kirwan JM, Symonds P, Green JA, et al. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol 2003;68:217–226. 7. Roeske JC, Lujan A, Rotmensch J, et al. Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2000;48:1613– 1621. 8. Portelance L, Chao KS, Grigsby PW, et al. Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation. Int J Radiat Oncol Biol Phys 2001; 51:261–266. 9. Lujan AE, Mundt AJ, Yamada SD, et al. Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:516–521. 10. Mundt AJ, Lujan AE, Rotmensch J, et al. Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2002;52:1330– 1337.
11. Brixey CJ, Roeske JC, Lujan AE, et al. Impact of intensitymodulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2002;54:1388–1396. 12. Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 2003;56:1354–1360. 13. Kidd EA, Siegel BA, Dehdashti F, et al. Clinical outcomes of definitive intensity-modulatedradiation therapy with fluorodeoxyglucose-positronemission tomography simulation in patients with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2010 Jul 15;77:1085–1091. 14. Welsh JS, Patel RR, Ritter MA, et al. Helical tomotherapy: An innovative technology and approach to radiation therapy. Technol Cancer Res Treat 2002;1:311–316. 15. Mackie TR, Kapatoes J, Ruchala K, et al. Image guidance for precise conformal radiotherapy. Int J Radiat Oncol Biol Phys 2003;56:89–105. 16. Kim YB, Kim JH, Jeong KK, et al. Dosimetric comparisons of three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and helical tomotherapy in whole abdominopelvic radiotherapy for gynecologic malignancy. Technol Cancer Res Treat 2009;8:369–377. 17. Yang R, Xu S, Jiang W, et al. Integral dose in three-dimensional conformal radiotherapy, intensity-modulated radiotherapy and helical tomotherapy. Clin Oncol (R Coll Radiol) 2009;21:706– 712. 18. Cozzarini C, Fiorino C, Di Muzio N, et al. Significant reduction of acute toxicity following pelvic irradiation with helical tomotherapy in patients with localized prostate cancer. Radiother Oncol 2007;84:164–170. 19. De Ridder M, Tournel K, Van Nieuwenhove Y, et al. Phase II study of preoperative helical tomotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 2008;70:728–734. 20. Hsieh CH, Wei MC, Lee HY, et al. Whole pelvic helical tomotherapy for locally advanced cervical cancer: Technical implementation of IMRT with helical tomotherapy. Radiat Oncol 2009;4:62.
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21. Mutic S, Dempsey JF, Bosch WR, et al. Multimodality image registration quality assurance for conformal three-dimensional treatment planning. Int J Radiat Oncol Biol Phys 2001;51:255– 260. 22. Miller TR, Grigsby PW. Measurement of tumor volume by PET to evaluate prognosis in patients with advanced cervical cancer treated by radiation therapy. Int J Radiat Oncol Biol Phys 2002;53:353–359. 23. Ahmed RS, Kim RY, Duan J, et al. IMRT dose escalation for positive para-aortic lymph nodes in patients with locally advanced cervical cancer while reducing dose to bone marrow and other organs at risk. Int J Radiat Oncol Biol Phys 2004; 60:505–512. 24. Potter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67–77. 25. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. JAMA 1958;53:25. 26. Kaatee RS, Olofsen MJ, Verstraate MB, et al. Detection of organ movement in cervix cancer patients using a fluoroscopic
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electronic portal imaging device and radiopaque markers. Int J Radiat Oncol Biol Phys 2002;54:576–583. Taylor A, Powell ME. An assessment of interfractional uterine and cervical motion: Implications for radiotherapy target volume definition in gynaecological cancer. Radiother Oncol 2008;88:250–257. Ahamad A, D’Souza W, Salehpour M, et al. Intensity-modulated radiation therapy after hysterectomy: Comparison with conventional treatment and sensitivity of the normal-tissuesparing effect to margin size. Int J Radiat Oncol Biol Phys 2005;62:1117–1124. van de Bunt L, van der Heide UA, Ketelaars M, et al. Conventional, conformal, and intensity-modulated radiation therapy treatment planning of external beam radiotherapy for cervical cancer: The impact of tumor regression. Int J Radiat Oncol Biol Phys 2006;64:189–196. Lim K, Kelly V, Stewart J, et al. Pelvic radiotherapy for cancer of the cervix: Is what you plan actually what you deliver? Int J Radiat Oncol Biol Phys 2009;74:304–312. Eifel PJ, Levenback C, Wharton JT, et al. Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1995;32:1289–1300.
doi:10.1016/j.ijrobp.2010.09.049
CLINICAL INVESTIGATION
Gynecologic Cancer
SPLIT-FIELD HELICAL TOMOTHERAPY WITH OR WITHOUT CHEMOTHERAPY FOR DEFINITIVE TREATMENT OF CERVICAL CANCER ALBERT J. CHANG, M.D., PH.D.,*k SUSAN RICHARDSON, PH.D.,* PERRY W. GRIGSBY, M.D., M.S.,*yzk xk AND JULIE K. SCHWARZ, M.D., PH.D.* *Department of Radiation Oncology, yDivision of Nuclear Medicine, Mallinckrodt Institute of Radiology, zAlvin J. Siteman Cancer Center, xDepartment of Cell Biology and Physiology, and kDivision of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO Objective: The objective of this study was to investigate the chronic toxicity, response to therapy, and survival outcomes of patients with cervical cancer treated with definitive pelvic irradiation delivered by helical tomotherapy (HT), with or without concurrent chemotherapy. Methods and Materials: There were 15 patients with a new diagnosis of cervical cancer evaluated in this study from April 2006 to February 2007. The clinical stages of their disease were Stage Ib1 in 3 patients, Ib2 in 3, IIa in 2, IIb in 4, IIIb in 2, and IVa in 1 patient. Fluorodeoxyglucose–positron emission tomography/computed tomography (FDGPET/CT) simulation was performed in all patients. All patients received pelvic irradiation delivered by HT and high-dose-rate (HDR) brachytherapy. Four patients also received para-aortic irradiation delivered by HT. Thirteen patients received concurrent chemotherapy. Patients were monitored for chronic toxicity using the Common Terminology Criteria for Adverse Events version 3.0 criteria. Results: The median age of the cohort was 51 years (range, 29-87 years), and the median follow-up for all patients alive at time of last follow-up was 35 months. The median overall radiation treatment time was 54 days. One patient developed a chronic Grade 3 GI complication. No other Grade 3 or 4 complications were observed. At last followup, 3 patients had developed a recurrence, with 1 patient dying of disease progression. The 3-year progression-free and cause-specific survival estimates for all patients were 80% and 93%, respectively. Conclusion: Intensity-modulated radiation therapy delivered with HTand HDR brachytherapy with or without chemotherapy for definitive treatment of cervical cancer is feasible, with acceptable levels of chronic toxicity. Ó 2012 Elsevier Inc. Cervix, Cancer, PET, IMRT, Tomotherapy.
ited data are available for IMRT treatment of gynecologic malignancies. Several dosimetric studies reported a decrease in volume of small bowel, bladder, and bone marrow irradiated in simulated IMRT treatment plans when compared with conventional two- or four-field treatment plans (7–9). Reductions in acute gastrointestinal (GI) and hematological toxicity have been demonstrated with IMRT in comparison with conventional four-field techniques for treatment of gynecologic malignancies (10, 11). A preliminary study demonstrated a reduction in late GI toxicity with pelvic IMRT (12). There has been only one prospective study that evaluated IMRT in patients with intact cervical cancer. That study included 135 patients who received pelvic IMRT delivered by a linear accelerator, and demonstrated a reduction in Grade 3 or greater bowel or
INTRODUCTION Concurrent chemoradiation is the standard of care for treatment of cervical cancer. Multiple trials have demonstrated improved survival along with decreased local and distant relapse rates with the addition of concurrent chemotherapy to radiotherapy (1–3). Increased acute hematological, gastrointestinal, and genitourinary side effects have also been observed with the addition of concurrent chemotherapy to radiotherapy (3–5). Limited data are available regarding the long-term side effects of concurrent chemoradiation. Late Grade 3 or 4 complications, including small bowel obstruction, fistula formation, proctitis, and hematopoetic suppression, occur at rates as high as 23% (6). Intensity-modulated radiation therapy (IMRT) has been increasingly used to reduce treatment-related toxicity. LimReprint requests to: Julie Schwarz, M.D., Ph.D., Washington University School of Medicine, Department of Radiation Oncology—Campus Box 8224, Mallinckrodt Institute of Radiology, St. Louis, MO 63110. Tel: (314) 362-8502; Fax: (314) 7479557; E-mail: [email protected] Conflict of interest: none.
Acknowledgment—This research was presented in poster form at the 2009 annual meeting of the American Society for Radiation Oncology (ASTRO). Received May 6, 2010, and in revised form Aug 2, 2010. Accepted for publication Sept 30, 2010. 263
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bladder complications with pelvic IMRT in comparison with the conventional two-field technique (13). Helical tomotherapy (HT) is a method of delivering IMRT that combines the function of a linear accelerator and a helical CT scanner into one unit (14, 15). Dosimetric studies have suggested improved organ-at-risk sparing for pelvic irradiation with HT in comparison to nonhelical IMRT (16, 17). There are limited studies demonstrating low rates of acute toxicity with pelvic irradiation by HT for treatment of prostate and rectal cancer (18, 19). Recently, Hsieh et al. reported treatment planning results and acute toxicities for 10 patients with cervical cancer treated with HT (20). In that study, HT was shown to be technically feasible, with acceptable short-term clinical outcomes and acute toxicities. The investigators also showed lower mean doses to the rectum, bladder, and intestines with the use of HT compared with conventional whole pelvis radiation treatment. The goal of the present study was to evaluate the long-term clinical outcomes and chronic toxicities for 15 patients treated with adaptive split-field HT for cervical cancer. METHODS AND MATERIALS Patients This study included 15 consecutive patients with newly diagnosed cervical cancer treated with radiation therapy with curative intent from April 2006 to February 2007 at the Mallinckrodt Institute of Radiology. Analysis of this prospective registry study was approved by the Washington University Human Research Protection Office. All patients underwent a complete pretreatment staging workup, including a history and physical examination, examination under anesthesia, cervical tumor biopsy, diagnostic abdominal and pelvic CT scan, and whole-body FDG-PET/CT. All patients had three gold seed fiducial markers placed within the cervix at the time of examination. Patients were staged using the International Federation of Gynecology and Obstetrics (FIGO) clinical staging criteria. A repeat PET/CT scan was performed 3 months after completing radiation treatment to evaluate response and any residual or progressive disease.
Simulation and treatment planning All patients were immobilized with a customized device (Alpha Cradle, Smithers Medical Products, North Canton, OH) to minimize daily setup variability. All patients underwent FDG-PET/CT simulation. Simulation scans were obtained from the level of T10 to mid-thigh. To minimize bladder activity, a Foley catheter was placed in the urinary bladder before receiving FDG. Patients received 20 mg furosemide intravenously approximately 20 min after FDG injection and received intravenous fluid administration (1,000–1,500 ml of 0.9% or 0.45% saline) during the study. All patients also underwent CT simulation on a Philips Brilliance CT Scanner (Philips Medical Systems, Cleveland, OH) with 3-mm slice thickness for localization and alignment. The FDG-PET/CT and CT simulation images were registered using point and anatomic matching (21). The metabolically active primary cervical tumor and involved lymph nodes were contoured with FDG-PET/CT guidance. The FDG-avid, metabolically active primary cervical tumor (MTVCERVIX) was defined as the 40% threshold volume(22). The common iliac vessels (e.g., nodal regions) were contoured from the bifurcation of the aorta, inferiorly
Fig. 1. Positron emission tomography (PET) fusion and intensitymodulated radiation therapy (IMRT) contours. (A) Fusion image of fluorodeoxyglucose–positron emission tomography (FDG-PET) and planning CT scan showing the FDG-avid lymph nodes and nodal clinical target volume (CTVNODAL) contour in a coronal view. (B) Axial view of CTVNODAL, MTVCERVIX, and FDG-avid lymph nodes. (C) Contours for CTVNODAL and MTVCERVIX in a three-dimensionally rendered coronal view.
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Table 1. Treatment planning parameters Structure Bladder Rectum Bowel Pelvic bones Femoral heads
Volume (%)
Dose guideline (Gy)
Maximum dose (Gy)
20 40 60 20 40 60 20 40 60 20 40 60 20
45 40 30 45 40 30 45 40 30 45 30 20 45
54
40 60
30 20
54 54 54 54
to the level of the medial circumflex artery, including the external and internal iliac vessels. These contours were expanded 7 mm, followed by subtraction of the pelvic bones, femoral heads, and vertebral bodies to create the clinical nodal target volume (CTVNODAL). A 7-mm margin was added uniformly to CTVNODAL to create the final planning target volume (PTVFINAL). Four patients received para-aortic irradiation, in 3 cases prophylactically and in 1 case for para-aortic nodal involvement noted on pretreatment FDGPET/CT. For patients receiving para-aortic irradiation, the upper border of CTVNODAL included the para-aortic lymph nodes and normal vessels with the contour originating from the aorta and vena cava at the level of the renal vessels and extending to the bifurcation of the aorta or top of the pelvic lymph node volume. Figure 1 shows representative contours for MTVCERVIX and CTVNODAL. Normal structures contoured included the following: bladder, rectum (up to sigmoid colon), spinal cord, right and left femoral heads, pelvic bones (consisting of sacrum, coccyx, ilium, ischium, pubic rami, and acetabulum). The ‘‘bowel’’ (a bag-like structure including the small and large intestines) was constructed by contouring the outermost extent of the bowel loops and the free space in-between the loops. This offers some allowance of bowel mobility (23). Treatment planning was performed using the TomoTherapy HIART System (version 2.2.1, TomoTherapy, Inc, Madison, WI). Plans were subject to the constraint of delivering 100% of the prescription dose to 95% of the planning target volume (PTV). Plans were optimized to minimize normal tissue dose to the bowel, rectum, bladder, pelvic bones, and femoral heads (Table 1). The prescription for PTVFINAL was 50.4 Gy in 1.8-Gy fractions and 20 Gy to the MTVCERVIX. For patients receiving para-aortic irradiation, the dose to the para-aortic nodes was 45 Gy for prophylaxis and 50 Gy for para-aortic nodal involvement. Figure 1 illustrates several contoured structures, along with the 95% isodose line generated for 1 patient using the above treatment planning parameters. Figure 2 shows an example tomotherapy dose distribution with isocontours from the 50-Gy and greater line (left) and the 20 Gy and greater line (right). The dose–volume histogram for this patient is shown in Fig. 3.
Patient treatment Patients were treated on TomoTherapy HI-ART Systems with daily megavoltage (MV) CT localization. Patients were set up to
Fig. 2. Dose distribution for a typical patient. The dose distributions illustrate our planning objectives to treat the lymphatics (PTV) to 50 Gy (left) and the MTV cervix to 20 Gy (right).
bony landmarks such as the spinal column and pelvic bones. After the daily image fusion, any patient requiring a greater than 2.0-cm shift in any direction underwent reimaging. All MVCT images were reviewed by the treating physician on a daily basis. Four times a week, ‘‘short’’ MVCT images were taken through the target and were approximately 10 cm in length (superior to inferior). Once a week, the patient had a ‘‘long’’ scan that covered all irradiated volumes and was approximately 20 cm in length. The short scans are adequate for aligning the patient to the isocenter and require less acquisition time. The long scans are useful for observing anatomical changes through the treated volume.
Chemotherapy and intracavitary brachytherapy Thirteen of 15 patients received concurrent chemoradiation therapy. Concurrent chemotherapy consisted of single-agent weekly cisplatin at 40 mg/m2 in 11 patients, weekly cisplatin 40 mg/m2, and infusional 5-fluorouracil 2 to 5 mg/m2 in 1 patient, and weekly
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histology. The median tumor size was 5 cm. In 5 of the 15 patients, the pelvic nodes were positive on pretreatment FDG PET/CT. Para-aortic lymph node involvement was noted in 1 patient. Of the patients, 73% completed all of their planned radiation treatments. Two patients did not complete radiotherapy for reasons unrelated to radiotherapy. One patient developed a brain metastasis during treatment and decided to not proceed with pelvic radiotherapy. One patient was hospitalized for sepsis and self-discontinued her treatment.
Fig. 3. Dose–volume historgram for the same patient as in Fig. 2. The planning target volume (PTV) is shown in blue, and the MTV is shown in red. carboplatin in 1 patient. Of the 13 patients receiving concurrent chemoradiation, 12 patients completed all planned chemotherapy cycles without any dose reduction. All patients received highdose-rate (HDR) brachytherapy delivered in six weekly fractions of approximately 6.5 Gy to Point A using an Iridium-192 source and Fletcher-Suit-Declos CT/MR compatible titanium intracavitary applicators (Varian Medical Systems, Palo Alto, CA). Patient treatment plans were developed on either 3D MRI or CT images. The 2-cc bladder and rectum doses were monitored according to the European Society for Therapeutic Radiology and Oncology guidelines (24). All patients were weighed before brachytherapy treatment. The median overall treatment time was 54 days. No treatment breaks were required.
Survival/recurrence The median follow-up for all patients was 35 months (range, 27–42 months). The 3-year cause-specific and progression-free survival estimates were 93% and 80%, respectively (Fig. 4). At the time of last follow-up, 9 patients were alive with no evidence of disease, whereas 3 patients had died of causes unrelated to their cancer. Three patients (20%) developed recurrences, two of which were distant only, and one of which was both local and distant. The single local failure occurred in a patient who presented with synchronous anal and cervical squamous cell cancers. She was prescribed 54 Gy to the anal tumor with 20 Gy to the MTV cervix and 50.4 Gy to the pelvic, paraortic, and inguinal lymph nodes. She also
Table 2. Patient characteristics and pathologic factors (N = 15) Characteristic
Toxicity assessment Follow-up examinations were performed approximately every 2 months for the first 6 months, every 3 months for the subsequent 2 years, and then every 6 months thereafter. Patients were evaluated for disease status and for the appearance of toxicity, with history and complete physical examinations in addition to laboratory and radiological tests. In most patients, FDG-PET was performed 3 months after completion of treatment and then yearly or when warranted by clinical examination or symptoms. Late complications were reported as events occurring after 90 days after completion of therapy. Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 was used to score the maximum late toxicity (http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf).
Statistical analysis Survival, tumor recurrence, and actuarial complication rates were measured from the completion of treatment. StatView Version 5.0.1 software (SAS Institute, Cary, NC) was used for the analysis. The Kaplan–Meier (product–limit) method was used to derive estimates of survival based on total sample size (25).
RESULTS Patient characteristics Fifteen consecutive patients with cervical cancer were treated definitively with curative intent using HT. The baseline characteristics of the entire cohort of patients are summarized in Table 2. Of the tumors, 86% were of squamous
Age, y, median (range) Follow-up, mo, median Stage (n; % of total) IB1 IB2 IIA IIB IIIA IIIB IVA Tumor diameter, cm, mean (range) #2 cm >2 cm to #4 cm $4 cm Not determined Pelvic lymph node involvement Positive Negative Para-aortic lymph node involvement Positive Negative Grade (n; % of total) 1 2 3 Undetermined Histology Squamous Adenocarcinoma Clear cell
Result 51 (29–87) 34 3 3 2 4 0 2 1 5 (2.23–6.46) 1 3 10 1
(20%) (20) (13) (27) (0) (13) (7) (7%) (21) (71)
5 10 1 14 2 9 3 1
(13%) (60) (20) (7)
13 1 1
(86%) (7) (7)
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Table 3. Late/chronic toxicities potentially related to chemoradiation therapy according to CTCAE v3.0 criteria Grade Toxicity
I
II
III
IV
V
Gastrointestinal Genitourinary Fracture Pain
3 0 0 2
2 2 0 0
1 0 0 0
0 0 0 0
0 0 0 0
para-aortic plus pelvic irradiation with concurrent weekly cisplatin. No other chronic Grade 3 toxicities were noted.
DISCUSSION
Fig. 4. Kaplan–Meier curves for (a) progression-free survival and (b) cause-specific survival.
underwent HDR brachytherapy for an additional 39-Gy boost to the cervical tumor. This patient experienced recurrence locally in two lymph nodes, one perirectal and one inguinal. These were detected radiographically, along with distant failures in the mediastinal and supraclavicular regions, 1 year after the completion of treatment. The inguinal lymph node was included in the 50.4-Gy PTV; the perirectal lymph node, which was not positive on pretreatment imaging, was located within the 30 Gy isodose line for the IMRT plan. This patient died 8 months later of disease progression. Toxicity Detailed chronic toxicities for the entire patient population (N = 15) are presented in Table 3. The majority of late toxicities were Grade 1 (33.3%) and Grade 2 (26.7%). There were 3 patients with chronic Grade 1 GI toxicities (1 constipation, 1 proctitis, 1 bleeding with no intervention necessary) and 2 patients with chronic Grade 1 pain. Four patients experienced chronic Grade 2 toxicities (1 rectal bleeding requiring minimal cauterization, 1 anorectovaginal fistula, and 2 cystitis). The patient with the Grade 2 anorectovaginal fistula also presented with a concomitant squamous cell carcinoma of the anus in addition to cervical cancer. One Grade 3 late effect (6.7%) was observed. This patient sustained a small bowel obstruction after receiving
In this study, we demonstrate that HT is a feasible method of IMRT delivery for definitive treatment of patients with intact cervical cancer. The local control rate at 36 months was 93%, with only one local failure among 15 patients. The median overall treatment time was 54 days, with no patients requiring a treatment break. When concurrent chemotherapy was administered in our study, 92% of patients completed all planned chemotherapy. Although this study was not designed for direct comparison with the conventional four-field technique, the rate of completion of chemotherapy is higher than the 49% rate of completion observed in patients receiving weekly cisplatin chemotherapy with two- or four-field conventional radiotherapy (2). The maximal benefit of combined radiation and chemotherapy may be realized with HT through minimization of radiation treatment breaks and alterations in the planned chemotherapy schedule. A preliminary study demonstrated that IMRT for treatment of gynecological malignancies reduced chronic GI toxicity when compared with conventional technique (12). This study had limited follow-up and included a heterogenous cohort of patients diagnosed with endometrial and cervical cancer, with some of the patients undergoing surgery. A recent publication from our institution demonstrated that nonhelical IMRT for intact cervical cancer reduced the rate of Grade 3 or greater bowel and bladder complications according to CTCAE v3.0 criteria when compared with the conventional two-field technique (6% vs. 17%) (13). Our rates of chronic toxicity in this current study are consistent with those published by Kidd et al., with only 1 patient (7%) experiencing a Grade 3 complication based on CTCAE v3.0 criteria. This patient received para-aortic plus pelvic radiation with concurrent cisplatin chemotherapy, which likely contributed to the toxicity. Concerns about target motion and deformation resulting in a geographic miss have limited the widespread use of IMRT for gynecologic cancer. A study demonstrating significant interfractional cervical tumor motion suggested a generous PTV margin to account for the target motion (26, 27), which can increase the volume of normal tissue irradiated and decrease the benefit of IMRT (28). However,
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Van de Bunt et al. found that IMRT is superior in the sparing of critical organs to conventional or conformal radiotherapy, even with bladder motion, rectal motion, and tumor regression considered (29). The advantage of using HT in our study was the ability for daily MVCT image registration with the treatment planning CT. Although all patients are set up based on bony landmarks, in our study, all patients received gold seed fiducial markers placed in the proximity of the cervical tumor (see Methods and Materials). This allowed us to monitor daily target motion on MVCT scans, and ensured consistency of patient setup and adequate CTV coverage. In addition, the treatment planning isodose line projection onto the MVCT scan allowed monitoring of any organs at risk (such as small bowel) that could dip into the highdose regions. Patient weight was also carefully monitored for any significant weight gain or loss. Although no patients in this study required it, in our clinic adaptive planning has been done for patients who had a significant weight change.With daily image guidance, a 5-mm PTV margin expansion has been suggested to be sufficient (30). In our study, we used a 7-mm PTV margin expansion.
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Our study is limited by a retrospective analysis of patient outcomes and a small patient population. To limit selection bias, we evaluated 15 consecutive patients with intact cervical cancer who were treated with HT, which resulted in an even distribution of patients ranging from Stage Ib1 to Stage IVa. Although our study reports the longest follow-up for HT in gynecologic cancer to date, it should be noted that Grade 3 or greater rectal and urinary complications can occur up to 25 years after treatment. Given that the majority of chronic complications from radiation therapy for gynecologic cancer occur within the first 3 years after the completion of therapy (31), it is likely that the majority of complications resulting from treatment have been accounted for within our followup period. CONCLUSION This study shows the feasibility of treatment of intact cervical cancer with split-field IMRT using HT, with low rates of chronic toxicity while maintaining excellent disease control.
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