The Emerging Use of IMRT for Treatment of Cervical Cancer

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  • 1 Department of Radiation Oncology, University of Washington Medical Center; Seattle Cancer Care Alliance, Seattle, Washington
  • 2 Department of Radiation Oncology, University of Washington Medical Center; Seattle Cancer Care Alliance, Seattle, Washington

Radiation therapy plays an important role in both the definitive and adjuvant treatment of patients with cervical cancer. However, although radiation therapy is effective in controlling tumor growth, associated acute and chronic adverse effects are well known. Intensity-modulated radiation therapy (IMRT) is increasingly being used to treat cervical cancer and has the potential to improve the therapeutic ratio because of its ability to escalate dose to cancer targets while sparing adjacent healthy tissue. Multiple dosimetric studies were initially performed, establishing the conceptual feasibility of IMRT in patients with cervical cancer. Subsequent early reported series of patients treated with IMRT showed dosimetric and clinical benefits, with reduction in acute gastrointestinal and hematologic toxicity compared with historic controls, particularly in the posthysterectomy setting. Consensus is evolving regarding the use of IMRT in treating cervical cancer, particularly in the posthysterectomy setting, and for dose escalation to para-aortic nodes and bulky sidewall disease. Target delineation in the context of internal organ motion and tumor shrinkage during a course of fractionated external-beam radiotherapy remains an area of active investigation. IMRT in treating cervical cancer in the setting of an intact uterus remains in its nascent stage and should be used judiciously only within clinical trials. Although not a routine substitute for brachytherapy, it may be considered as a boost for highly selected patients who are not brachytherapy candidates.

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Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe potential advantages and disadvantages of pelvic IMRT
  • Describe technical strategies that may improve the therapeutic ratio of IMRT
  • Describe clinical scenarios for which IMRT is indicated and those for which it is less useful

In 2010, the American Cancer Society (ACS) has estimated that 12,200 cases of uterine cervical cancer will be diagnosed and 4210 deaths will occur from the disease in the United States.1 Worldwide, the most recent yearly ACS estimate of cervical cancer cases was 555,094, with an associated 309,808 deaths.2 Among women globally, cervical cancer is second only to breast cancer in incidence, and third after breast and lung cancers with regard to mortality.

For many of these women, radiation therapy plays an important role in both the definitive and adjuvant (i.e., posthysterectomy) treatment setting. Definitive pelvic radiotherapy with concurrent platinum-based chemotherapy and brachytherapy boost has been established as the standard of care in locally advanced disease. In 1999, the publication of 5 randomized trials37 led to the February 1999 NCI recommendation to consider concurrent platinum-based chemoradiation as primary therapy for patients with locally advanced cervical cancer. In the setting of clinical early-stage disease after radical hysterectomy, adjuvant pelvic radiotherapy is recommended, depending on the extent of cervical stromal invasion, lymphovascular space invasion, and tumor size, although adjuvant chemoradiation is recommended in the setting of positive lymph nodes after radical hysterectomy, involved parametria, or positive surgical margins.

Although radiation therapy maintains an effective track record in controlling locoregional tumors, associated acute and chronic adverse effects are wellknown. Nausea, vomiting, diarrhea, irritation of the urinary tract, and bone marrow suppression are common side effects experienced by patients undergoing pelvic radiotherapy. Furthermore, these side effects are enhanced with the administration of concurrent chemotherapy. In the acute setting of chemoradiation, low-grade genitourinary, gastrointestinal, and hematologic toxicity have been reported, with respective rates of 17.5%, 45.2%, and 53.3%. High-grade acute effects (3 or 4) are less common, but rates of 1.5% genitourinary, 8% gastrointestinal, and 27.6% hematologic toxicity have been noted.8

In the longer term, anatomic and physiologic alterations, such as obstruction and strictures, fistulization, pelvic insufficiency fracture, soft tissue fibrosis or necrosis, and lymphedema, are potential causes of severe morbidity. Although less well documented than acute toxicities, incidence of late grade 3 and 4 complications have ranged from 6% to 23.3% of patients.8 Most clinical trials have historically underemphasized late low-grade (i.e., grade 1 and 2) effects, but with recent increased emphasis on long-term quality of life, experts have recognized that this low-grade late toxicity (e.g., anal leakage) can be prevalent.9

The external beam component of radiation therapy has evolved dramatically in the past 2 decades and is now capable of differentially targeting tumor and normal tissues in the pelvis. Traditional anteroposterior and “4 field box” radiation therapy plans based on bony landmarks have been shown to inadequately address intended targets in many cases,10 leading to the widespread implementation of 3-dimensional conformal treatment planning, facilitated with modern cross-sectional imaging.

Intensity-modulated radiation therapy (IMRT) has potential to further improve the therapeutic ratio of external-beam radiotherapy. The improved conformality achievable with IMRT can potentially mitigate adverse effects and, in some clinical scenarios, allow dose to be escalated to target volumes to optimize tumor control. Traditionally, whole-pelvic doses are limited to 45 to 50 Gy, primarily as a result of small bowel tolerance. In this dose range, greater volumetric sparing of small bowel with IMRT will reduce the risk of acute and late toxicity. Conversely, IMRT may also permit selective boosting of gross disease sites to higher tumoricidal doses, without a corresponding increase in small bowel dose.

The use of IMRT has increased dramatically over the past decade. The percentage of practicing radiation oncologists using IMRT increased from 32% in 2002 to 73% in 2004.11,12 In the upper pelvis, IMRT increases sparing of the small bowel (particularly in the posthysterectomy setting) and bone marrow of the iliac wings (Figure 1). In the low pelvis, IMRT better spares the bladder, rectum, and femoral heads (Figure 2). The authors have used IMRT in selected posthysterectomy pelvic irradiation cases, in dose escalation for grossly positive para-aortic lymph nodes, in patients unfit for brachytherapy, and in reirradiation cases.

Figure 1
Figure 1

Upper pelvis axial CT planning image for an intensity-modulated radiation therapy (IMRT) dose plan in a patient status post radical hysterectomy with a positive resected pelvic lymph node undergoing concurrent chemoradiation. Nodal planning volume and small bowel are outlined. The prescription 5040 cGy representing the 100% isodose as well as the 110%, 105%, 98%, 95%, 89%, 69%, and 50% isodose lines are shown.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0106

Technical Factors

IMRT has been made possible through advancements in high-definition cross-sectional imaging and dose algorithm computing, which were first pioneered and widely applied in the setting of head and neck, and prostate cancers. The use of IMRT requires precise delineation of target volumes and organs at risk (OARs). Dose is prescribed not to a single point or fixed volume but to a “best fit” based on dose–volume objectives. Dose to a cancer-bearing region is understood and reported in terms of gross target volume (GTV), clinical target volume (CTV = GTV + potential microscopic regions at risk), and planning target volume (PTV = CTV + margins for patient and organ movement and daily set-up reproducibility). The prescription is optimized based on physician defined dose–volume constraints, specified for both target volumes and OARs. Significantly more time and resources by physicians, physicists, and technical staff are required for IMRT planning and delivery, compared with conventional 3-dimensional treatment approaches. Tumor target volumes are delineated by correlation of imaging and physical examination findings, supplemented with a clear understanding of locoregional pathways of spread, and are often expanded asymmetrically based on the juxtaposition of adjacent normal tissues and anatomical barriers to tumor extension. Individual organs at risk within the planned irradiated volume must be contoured, and appropriate dose–volume constraints determined.

Figure 2
Figure 2

Lower pelvis axial CT planning image for an intensity-modulated radiation therapy (IMRT) dose plan in a patient status post radical hysterectomy with a positive resected pelvic lymph node undergoing concurrent chemoradiation. Planning target volume, rectum, vagina, and bladder are outlined. The prescription 5040 cGy representing the 100% isodose as well as the 110%, 105%, 98%, 95%, 89%, 69%, and 50% isodose lines are shown.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0106

A “good” IMRT plan appropriately optimizes target volume and OAR constraints to maximize the therapeutic ratio, through multiple iterations using a computer inverse algorithm and through multistep physician feedback after review of computer-generated isodose plans and dose–volume histograms.13 Adhering to the complex treatment and dosimetric plans developed, dosing and linear accelerator setup specifications are then controlled with sophisticated computer algorithms, in which the target volume achieves its ultimate intended dose through the integration of multiple fragmental portions of radiation exposure. At no single timepoint is the entire target volume delivered at a homogenous dose. With the numerous beam segments and subsegments used for IMRT delivery, obtaining portal imaging that shows the entire irradiated volume is impractical or impossible. Therefore, any clinical IMRT delivery, meticulous quality assurance measurements using diodes and ion chambers must be performed to calibrate and confirm each patient plan.

Table 1

Intensity-Modulated Radiation Therapy Studies for Pelvic Irradiation

Table 1

Dosimetric Feasibility and Clinical Applicability

Dosimetric analyses and clinical patient series have examined the potential of IMRT to limit adverse effects associated with pelvic radiotherapy (Table 1). Dosimetric studies initially set the foundation for IMRT use, showing substantially less volume of small bowel, bladder, rectum, and bone marrow receiving a given prescription pelvic dose than with conventional external-beam plans,1418 and further extrapolated benefits of normal tissue sparing while allowing dose escalation to the tumor in the setting of positive para-aortic lymph nodes.19

Mundt et al.20,21 reported the first clinical series of 40 patients treated with whole-pelvis IMRT in 2001, most of whom were posthysterectomy, compared with 35 historic controls treated with conventional fields. Grade II acute gastrointestinal toxicity was less common with IMRT (60% vs. 91%; P = .002), with 75% of patients requiring no or only infrequent antidiarrheal medications compared with 34% of patients treated with traditional fields (P = .001). Acute hematologic toxicity in patients treated concurrently with chemotherapy was significantly less, and chemotherapy was withheld or delayed less often in patients treated with IMRT (40% vs. 12.5%; P = .06), attributed to less iliac crest bone marrow volume being irradiated.22 Chronic gastrointestinal toxicity 1 year after treatment was also decreased with IMRT.23

Other published studies have described the treatment of patients with extended-field IMRT for dose escalation to para-aortic nodes.2426 Salama et al.24 reported on toxicity in 13 patients treated with extended-field IMRT for gynecologic malignancies (11 of whom were posthysterectomy). Patients received 45 Gy in 1.8-Gy daily fractions, with an additional 9-Gy boost to bulky nodes, in the para-aortics or pelvis. Two patients developed acute grade III toxicity, both of whom were treated with concurrent weekly cisplatin chemotherapy. Two patients experienced late toxicity in the context of their overall therapeutic course: 1 had undergone multiple prior abdominal surgeries and experienced a small bowel obstruction requiring partial colectomy, and the other had grossly involved common iliac nodes and developed bilateral lower-extremity edema.24

Gerszten et al.26 similarly showed feasibility of extended-field coverage with IMRT, using a simultaneous integrated boost technique involving 45 Gy delivered in 25 fractions to the entire target volume, with simultaneous boost to 55 Gy to involved nodes in the same number of fractions. No patients experienced acute grade III or IV toxicity.

Beriwal et al.25 reported on 36 patients treated with extended-field IMRT for cervical carcinoma. Para-aortic nodes were treated to the superior L1 vertebral border. The treatment was found to be well tolerated, with acute grade III or greater gastrointestinal and genitourinary toxicity seen in only a single patient each. Although ultimate distant failure occurred in 9 patients, only 2 experienced relapse within the irradiated volume (1 pelvic, 1 para-aortic).

Overall, these studies have shown dosimetric and suggested clinical benefits with pelvic IMRT, with reduced acute gastrointestinal and hematologic toxicity and decreased long-term gastrointestinal toxicity. IMRT also enabled better tolerance of concurrent chemotherapy. Furthermore, several patient series have shown the feasibility of IMRT in achieving tolerable dose escalation to involved para-aortic lymph nodes.

Challenges

Target delineation in the context of internal organ motion and tumor shrinkage during a course of fractionated external-beam radiotherapy treatment poses challenges to treatment with IMRT, with the implied limited target margins. The bladder, rectum, and other bowels are dynamic and mobile structures in the pelvis in direct proximity to target structures. Bladder and rectal filling can vary dose distribution to these normal structures and alter GTV position.27,28 Tumor deformation can alter the arrangement of surrounding normal tissues. Tumor regression during treatment is a fortunate, though complex, reality and renders target definition based on a single preradiation CT scan less dependable.

Serial MRI has been used to characterize motion of the uterus and cervix.29 One dosimetric study found that margins of 4 cm at the fundus and 1.5 cm at the cervical os were necessary to encompass 90% of interscan motion.30 Another article suggested that 2-cm PTV expansions led to statistically similar coverage of targets compared with a “4 field box”; however, significant underdosing occurred in 1 patient who displayed excessive internal target movement. In a study evaluating patients with MRI before and weekly during IMRT, additional margins were required to accommodate 95% of movement in multiple dimensions.31

Rapid involution and mobility of carcinoma of the cervix in response to radiotherapy has been described in multiple studies. Lee et al.32 described 50% tumor regression at approximately 21 days at a median radiation dose of 30.8 Gy. Van de Bunt et al.33 reported that after 30 Gy, the primary GTV decreased an average of 46%. Replanning with IMRT significantly diminished the treated bowel volume if the primary GTV decreased by 30 cm3.33 Beadle et al.34 showed mean volume reduction of 62.3% after 45 Gy.

Altogether, although IMRT offers potentially superior planned dose distribution, its superiority remains dependent on accurate delivery of fields and avoidance of possible heterogenous hot or cold spots within the irradiated volume. Further adding complexity is the dynamic environment of the pelvis; patient movement, cancer target movement, normal structure movement, and tumor shrinkage during treatment are all important factors to consider when delineating treatment plan specifications. Planning appropriate target margins given internal target motion and variability is a challenge, and remains particularly undefined in the intact uterus setting, where the fundus movement may be appreciable and gross temporal tumor regression significant. Image-guided radiation therapy (IGRT), including the use of regular cone-beam CT, may help improve and verify localization and positioning during a course of IMRT.

Cooperative Group Trials

The Radiation Therapy Oncology Group (RTOG) has completed accrual for RTOG-0418, a phase II trial evaluating the use of pelvic IMRT in the posthysterectomy setting for patients with endometrial or cervical carcinoma. Objectives for this study include testing the hypothetical reduction in short-term bowel injury and estimating the rates of locoregional control, disease-free survival, overall survival, and chemotherapy compliance. Furthermore, the trial was designed to evaluate IMRT feasibility, reproducibility, and ability to assess dosimetry plans in clinical trials across multiple institutions. The vaginal planning target volume was derived from an internal target volume (ITV) with a 7-mm expansion. The ITV was based on fused full and empty bladder scans, allowing for a composite vagina and paravaginal soft tissue volume, taking into account the variation of the target caused by bladder filling and motion. The nodal CTV included internal, external, and common iliac lymph nodes. If the cervix was involved, presacral lymph nodes were included down to S3. Preliminary analysis showed general feasibility for the use of IMRT in multi-institutional trials when stringent guidelines are specified.35

Cervical cancer clinical trials continue to use IMRT. The RTOG 0724 trial evaluating adjuvant therapy for lymph node–positive cervical cancer and Gynecologic Oncology Group (GOG) 263 for lymph node–negative cervical cancer allow IMRT, again with carefully detailed guidelines of application. Both the RTOG and GOG protocols specify a vaginal ITV as a composite volume derived from fused full and empty bladder scans.

Consistency in volume and contouring definitions is essential among centers using IMRT in multicenter trials. The RTOG atlas “Consensus Guidelines for the Delineation of the CTV in the Postoperative Pelvic Radiotherapy of Endometrial and Cervical Cancer” for posthysterectomy contouring is available at http://www.rtog.org/pdf_document/GYN-Atlas.pdf.

The role of IMRT in treating intact cervical cancer remains even more nascent and investigational, and should be performed only in prospective clinical trials. Target mobility and tumor deformation/regression during a course of radiotherapy are of greater concern in intact cancer cases than in the posthysterectomy setting. A preliminary attempt at target volume consensus in intact cervical cancer (based on a single case study) was recently published.36 MR imaging with fusion of the T2-weighted axial images to the planning CT is strongly recommended. The CTV includes the GTV, remaining cervix, entire uterus, parametria, ovaries, vaginal tissues, and nodal region, varyingly comprised of the common, internal iliac, external iliac, obturator, presacral, and para-aortic nodes, depending on the extent of disease. PTV margins of 1.5 to 2 cm around the primary CTV are recommended if good-quality daily soft tissue verification is available and a 7-mm margin is present around the nodal CTV. If daily verification with bone landmarks is performed instead, more generous PTV margins are required. Based on this target delineation analysis, phase II trials for IMRT in intact cervical cancer have been proposed.

Conclusions

Consensus is evolving, founded in a decade of published studies and evidenced by its adoption in cooperative group trials, that IMRT has clear applicability in cervical cancer, particularly in the posthysterectomy setting. IMRT offers distinct dosimetric advantages over traditional 2- and 3-dimensional planning techniques with regard to sparing normal tissues adjacent to cancer targets. The use of IMRT in a multicenter cooperative group trial has been tested and found to be feasible in posthysterectomy cases. The hope is that further study of IMRT will continue to confirm that patients undergoing surgery followed by adjuvant radiation with or without chemotherapy will experience excellent locoregional cancer control and decreased short- and long-term toxicity. Furthermore, IMRT allows dose escalation to para-aortic lymph nodes and bulky sidewall disease, and may be useful in reirradiation cases. IMRT may also be considered as a boost to primary disease in patients who are not brachytherapy candidates. However, application of IMRT for cervical cancer in the setting of an intact uterus and cervix remains in its nascent stage and should not be accepted as a routine substitute for brachytherapy.

IMRT remains a complex and heterogeneous technique. Treatment planning options, including the number of incident beams, beam angles, target volumes, and normal tissue constraints, render it a flexible and powerful tool. However, it is also subject to inadvertent inadequate dose coverage or overdose caused by target motion or suboptimal target delineation. Furthermore, with implementation of inverse planning techniques, the physician designates “intuitive” dose delivery control to the computer, thus requiring rigorous treatment planning and delivery quality assurance procedures. High-quality imaging and image interpretation are imperative for high-fidelity treatment delivery. The intra- and interfraction motion described earlier suggest a role for a daily 3-dimensional image-guided setup, particularly in emerging areas of study for treating the intact cervix.

The way forward is through continued evolution within clinical trials. With regard to cancer control, normal tissue impact, and long-term assessment of quality of life, further prospective multi-institutional studies will help establish the ultimate role of IMRT in cervical cancer management.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

CME AUTHOR

Laurie Barclay, MD, Freelance writer and reviewer, Medscape, LLC

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

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Correspondence: Wui-Jin Koh, MD, Department of Radiation Oncology, University of Washington Medical Center, Seattle Cancer Care Alliance, 825 Eastlake Ave E., G1101, Seattle, WA 98109-1023. E-mail: wkoh@u.washington.edu

Disclosure: Christopher Loiselle, MD, has disclosed no relevant financial relationships.

Disclosure: Wui-Jin Koh, MD, has disclosed no relevant financial relationships.

Supplementary Materials

  • View in gallery

    Upper pelvis axial CT planning image for an intensity-modulated radiation therapy (IMRT) dose plan in a patient status post radical hysterectomy with a positive resected pelvic lymph node undergoing concurrent chemoradiation. Nodal planning volume and small bowel are outlined. The prescription 5040 cGy representing the 100% isodose as well as the 110%, 105%, 98%, 95%, 89%, 69%, and 50% isodose lines are shown.

  • View in gallery

    Lower pelvis axial CT planning image for an intensity-modulated radiation therapy (IMRT) dose plan in a patient status post radical hysterectomy with a positive resected pelvic lymph node undergoing concurrent chemoradiation. Planning target volume, rectum, vagina, and bladder are outlined. The prescription 5040 cGy representing the 100% isodose as well as the 110%, 105%, 98%, 95%, 89%, 69%, and 50% isodose lines are shown.

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