International Journal of Gynecological Cancer:
Advances in Clinical Research in Gynecologic Radiation Oncology: An RTOG Symposium
Gaffney, David MD, PhD*; Mundt, Arno MD†; Schwarz, Julie MD, PhD‡; Eifel, Patricia MD§
*Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT; †Department of Radiation Oncology, University of California San Diego, San Diego, CA; ‡Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO; and §Department of Radiation Oncology, M. D. Anderson Cancer Center, Houston, TX.
Address correspondence and reprint requests to David Gaffney, MD, PhD, Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle of Hope, Rm 1570, Salt Lake City, UT. E-mail: firstname.lastname@example.org.
Conflict of interest statement: Dr. Mundt reports 2 Varian-sponsored research grants, a master research agreement with Varian, and participation in their speaker bureau. There are no other potential conflicts to report.
Copyright notification: All 3 tables are used with permission from previous publications. We have written notification of permission and will provide it when necessary.
Received June 6, 2011
Accepted December 20, 2011
Abstract: There have been inexorable improvements in gynecologic radiation oncology through technologically advances, 3-dimensional imaging, and clinical research. Investment in these 3 critical areas has improved, and will continue to improve, the lives of patients with gynecologic cancer. Advanced technology delivery in gynecologic radiation oncology is challenging owing to the following: (1) setup difficulties, (2) managing considerable internal organ motion, and (3) responding to tumor volume reduction during treatment. Image guidance is a potential route to solve these problems and improve delivery to tumor and sparing organs at risk. Imaging with positron emission tomography–computed tomography and magnetic resonance imaging are contributing significantly to improved accuracy in diagnosis, treatment, and follow-up in cancer of the cervix. Functional imaging by exploiting tumor biology may improve prognosis and treatment. Clinical trials have been the greatest mechanism to improve and establish standards of care in women with vulvar, endometrial, and cervical cancer. There have been multiple technological advances and practice changing trials within the past several decades. Many important questions remain in optimizing care for women with gynecologic malignancies. The performance of clinical trials will be advanced with the use of consistent language (ie, similar staging system and criteria), eligibility criteria that fit the research question, end points that matter, adequate statistical power, complete follow-up, and prompt publication of mature results.
IMAGE GUIDANCE AND MOTION MANAGEMENT IN GYNECOLOGIC RADIATION ONCOLOGY
Major advances in gynecologic radiation oncology in the past several decades have been through technologically advances, 3-dimensional imaging, and clinical research. Investment in these 3 critical areas has improved, and will continue to improve, the lives of patients with gynecologic cancer. Delivery of radiation therapy (RT) with advanced technology in gynecologic radiation oncology is challenging because of the following: (1) setup difficulties, (2) managing considerable internal organ motion, and (3) responding to tumor volume reduction during treatment.
Setup problems are only partially addressed with traditional immobilization approaches such as body vacuum lock devices or alpha cradles. Internal motion has been shown to be unpredictable and highly variable between patients. Additionally, organ motion and organ deformation of the uterine body and cervix can be extremely complex. In one study of patients with cervical cancer, 11% of the patients had a change from an anteverted uterus to a retroverted position adjacent to the rectum.1 Additionally, there are significant tumor volumetric reductions due to therapy. Tumor shrinkage can be rapid, variable, and significant.2 Positron emission tomography (PET) imaging and serial clinical evaluations and have demonstrated cervical primary tumor volume reductions with a half-life of 20 and 21 days, respectively.3,4 Serial computed tomographic (CT) scanning has shown concordant findings with a 63% volume reduction after 45 Gy,5 and a magnetic resonance imaging (MRI) study revealed a 46% volume reduction after 30 Gy.2 Organ motion and significant and rapid tumor volume reduction mandate diligence in the successful application of modern RT delivery technologies.
Image guidance is a potential route to solve these problems and improve delivery to tumor and sparing organs at risk. There is a myriad of image-guided RT (IGRT) technologies available (Table 1). These technologies allow safe and reproducible treatments. Strategies to solve setup problems, organ motion, and reproducibility include ultrasound, video-based imaging, planar x-ray, and volumetric imaging. These approaches have gained popularity; however, their principles are not new. At Karolinska University, a cobalt unit with in-room planar kilovoltage imaging was used as early as 1957. Similar approaches were developed at Princess Margaret Hospital in 1959 and the Netherlands Cancer Institute in 1960. Image-guided RT technologies allow volumetric assessment of the soft tissue targets and bony structures. Simpson et al6 performed a recent survey of 1600 radiation oncologists. Ninety-four percent used some form of IGRT on their patients. Most of the radiation oncologists used IGRT infrequently or rarely, and the predominant sites for IGRT included prostate cancer, head and neck cancer, tumors of the central nervous system, and lung cancer. The most frequent modalities used were volumetric approaches. Megavoltage planar was used in 63% of the respondents, kilovoltage planar in 58% of the respondents, ultrasound in 22% of the respondents, and video approaches in 3% of the respondents. As a disease site, gynecologic cancers were the sixth most common site, and 58% of the respondents used IGRT in their patients with gynecologic cancer. Image-guided RT incorporation has been rapid over the past decade: in 1999, approximately 10% of radiation oncologists were using IGRT, and this has increased to more than 90% a decade later.6
For the treatment of cervical cancer with IMRT, there are separate issues relating to intact advanced cervical cancer and posthysterectomy treatment. In intact cervical cancer, there can be large and unpredictable movement of the cervix and uterus, in addition to dramatic tumor regression; whereas in the posthysterectomy cases, the upper vagina can move significantly owing to variable bowel and bladder filling. In both cases, selection of margins is of paramount importance. There are 2 fundamental IGRT strategies: static approaches delineating a clinical target volume (CTV) and applying a planning target volume margin to encompass organ motion, and adaptive radiotherapy to account for motion and tumor changes. Six different studies have evaluated the required static margins for intact cervical cancer treatment (Table 2). Different imaging modalities and frequencies have been used. The proposed margins are frequently large (11–40 mm in size) given the motion of the uterine fundus.5,7–9 Other groups have proposed asymmetric margins given differential motions of the cervix and uterus.10,11 One recent report described daily online cone beam CT to assess interfraction motion in 10 patients with intact cervical cancer.12 A uniform CTV expansion of 15 mm would have failed to encompass the CTV in 32% of fractions; and owing to high interpatient variation, uniform margins of greater than 35 mm would be required to encompass the entire CTV for every fraction in every patient. All of these studies have relatively small sample sizes, and the uncertainty of the calculated margins is consequently large. Larger databases with sophisticated statistical approaches are needed to validate the use of asymmetric margins and provide clinical recommendations.
Adaptive IGRT is promising in cervical cancer given the large fluctuations in internal organ motion. In one MRI study that replanned midway through treatment, rectal sparing was noted for patients who had greater than 30 cc gross tumor volume regression.2 One recent study described 10 patients with cervical cancer with daily cone beam CT that underwent replanning after 30 Gy. Dose to the rectum was improved in 4 patients, unchanged in 3 patients, and worse in another three patients. Another approach is to have a library of treatment plans available from which the optimal plan is selected on the day of treatment. Machine learning approaches can be used with training data sets to establish a plan library so that subsequently, correct plans can be selected. Feedback loops can be used to inform the training set. With high throughput methods and the use of graphic processing units, it is possible that a new radiotherapy plan could be generated in well less than a minute, making adaptive radiotherapy possible, feasible, and manageable in the clinical setting.13 This has significant implications for all patients undergoing daily cone beam CT imaging.
Gynecologic tumors present significant challenges for the successful implementation of modern radiotherapy techniques. Creative and diligent approaches by radiation oncologists and physicists have demonstrated potential solutions. Moderate imaging is central in the key to overcoming these hurdles.
IMAGING ADVANCES IN GYNECOLOGIC RADIATION ONCOLOGY
Imaging is useful to determine extent of disease, to evaluate prognosis, to measure early and late response to treatment, and is currently being investigated as part of routine surveillance. In cervical cancer, the International Federation of Gynecology and Obstetrics (FIGO) staging system is a clinical staging system, and advanced imaging is not permitted. However, in facilities where advanced imaging (CT, MRI, or PET/CT) is available, it should be used to determine the extent of disease, individualize treatment, and minimize morbidity. Positron emission tomography has been shown to be sensitive for detecting lymph node involvement in carcinoma of the cervix, and the extent of lymph node involvement correlates inversely with prognosis (Fig. 1).14,15 In one institutional experience of more than 700 patients with cervical cancer who underwent pretreatment fluorodeoxyglucose (FDG) PET/CT scanning, CT detected that lymph node involvement in the pelvis occurred in 22% of patients, whereas PET detected lymph node involvement in 60% of the patients. Similarly, involved para-aortic lymph nodes were detected by CT in 6% of the patients, compared to 18% by PET. Additionally, PET detected occult supraclavicular nodal involvement in 6% of patients who were not detected by CT. Eighty percent of PET-positive lymph nodes are less than 1 cm in size, which is below the limit of CT/MRI resolution for detecting positive lymph nodes by size criteria. Additionally, 38% of patients with positive para-aortic lymph nodes had occult supraclavicular nodal involvement. Treatment changes occur in 30% to 50% of patients owing to PET findings. In addition to identifying lymph node status, other uses of FDG PET include defining a metabolically active tumor volume using maximum standardized uptake value as a biomarker for prognosis, evaluating tumor heterogeneity, and measuring rapidity, completeness, and durability of response. Metabolic tumor volume and maximum standardized uptake value correlate inversely with survival.16,17
Most oncologists favor MRI for accurate assessment of cervical tumor diameter and volume. T2-weighted images are typically used. Magnetic resonance imaging adds additional important information to the relatively inaccurate tumor assessment by FIGO staging.18,19 In a prospective study, MRI performed better than CT for imaging the primary tumor.20,21 Specifically, MRI was better for detection of parametrial involvement and for measuring tumor diameter. However, the study by Burghardt et al22 demonstrated a high correlation of histologic tumor volume with MRI-based tumor volume. It should be emphasized that MRI findings alone cannot be used to change clinical stage according to FIGO. According to a recent review, common imaging pitfalls include bulky exophytic tumors that significantly distend the vagina, overestimation of parametrial invasion with large tumors due to stromal edema, overestimation of infiltration of upper vagina, collapsed vaginal walls obscuring inferior tumor borders, concurrent endometriosis or cysts, cystic tumors, and postbiopsy hemorrhage.23 Minor loss of the fat plane between the tumor and bladder and/or rectum does not prove organ invasion, and bullous edema observed during cystoscopy does not permit a case to be allotted to stage IVA.
Magnetic resonance imaging can be used as a biomarker. Dynamic contrast-enhanced MRI can be used to evaluate tissue vascularity and perfusion, and diffusion-weighted imaging/apparent diffusion coefficient maps can evaluate cellularity and membrane integrity for cancers of the cervix. A recent study showed that the apparent diffusion coefficient correlates with response to chemoradiotherapy.24 Positron emission tomography is a sensitive indicator for early response to chemoradiation.25 Elegant studies by Mayr and colleagues26,27 have demonstrated that MRI can be used to detect early treatment response and predict ultimate therapy outcome as well.
Activity on posttreatment PET scans performed at Washington University (on average, 3 months after chemoradiation) correlate strongly with prognosis. Schwarz et al28 has demonstrated with PET scans the increasing poor prognosis for progressive disease, persistent disease, and lymph node status pretreatment as demonstrated by hazard ratios of 33, 6.3, and 3.5, respectively (Fig. 2). On multivariate analysis, both pretreatment lymph node status and posttherapy FDG response remained highly significant.28,29 The early treatment monitoring using functional/metabolic imaging has the clinical benefit of detecting recurrence much earlier than traditionally possible. Previously, salvage therapy was largely dependent on the identification of recurrences by clinical symptoms, making early identification of failure challenging. Salvage treatment for recurrence therefore consisted of either radical exenteration or remained purely palliative. With earlier detection of failure, less radical approaches for salvage surgery might be possible. One therapeutic paradigm is for patients who have persistent uptake only within the cervix or uterus to proceed to a cervical biopsy. For negative biopsies, patients could continue with clinical follow-up, whereas, if positive, they could undergo a salvage hysterectomy plus or minus lymph node dissection at that time. Additionally, if patients have new sites or progressive disease, they could proceed to palliative chemotherapy. Studies have demonstrated that when patients are symptomatic, most of those recurrences are PET positive. If recurrences in asymptomatic patients are detected early by FDG-PET, the survival rate is improved (Fig. 3).29
CLINICAL RESEARCH IN GYNECOLOGIC RADIATION ONCOLOGY: FUTURE QUESTIONS
There have been multiple technological advances and practice changing trials within the past several decades. Diagnostic imaging has resulted in our ability to assess tumor volume via CT, MRI, or PET. External beam radiotherapy planning delivery has become more conformal, and image guidance is widely used.6 Advances in brachytherapy have resulted in increased normal tissue sparing.30 There has been an evolution in applicator types, and more sophisticated delivery systems are used, including inverse planning for brachytherapy. Additionally, although cisplatin is the most frequent chemotherapy used concomitantly with radiation in cancer of the cervix, a wide array of systemic agents could potentially be used.31
There are many nuances in performing and reporting clinical trials. The importance of long-term follow-up on phase 3 gynecologic clinical trials is demonstrated by the postoperative radiation trial in vulvar carcinoma by Homesley et al.32 Initially, a highly significant survival benefit (P = 0.004) was observed, leading to early closure of the trial. However, in an update published more than 25 years later by Kunos et al,33 the difference in overall survival was no longer significant (P = 0.2; hazard ratio = 0.6). This trial still showed a reduction in cancer-related deaths, emphasizing the contribution of non–cancer-related deaths in clinical trials with long follow-up.
For cancer of the cervix, the National Cancer Institute published a clinical alert in 1999 after 5 trials evaluating cisplatin-based concurrent chemoradiotherapy demonstrated a marked improvement in overall survival.34,35 A patterns of care study performed in Canada demonstrated the rapid adoption of chemoradiotherapy.36 A meta-analysis confirmed the survival benefit of platinum-based chemoradiotherapy; however, it also showed a survival improvement for non–platinum-based chemoradiotherapy.31 This meta-analysis suggested a possible improvement in survival for patients receiving extended adjuvant chemotherapy, although the numbers of contributing studies and patients were small. The value of extended adjuvant chemotherapy after the concurrent radiation and chemotherapy course is currently being tested in multiple international phase 3 trials (Table 3).
Although a number of clinical trials in gynecologic cancer have changed practice and improved care, investigators have often found it very difficult to complete phase 3 trials. Phase 3 trials in cervical and vulvar cancer that did not meet accrual goals have included radical hysterectomy plus or minus neoadjuvant chemotherapy in stage IB2 carcinoma of the cervix (Gynecologic Oncology Group [GOG] 141), continuous infusion of 5-fluoruracil versus weekly cisplatin (GOG 165), radiotherapy plus or minus weekly cisplatin in node-positive vulvar cancer (GOG 185), addition of erythropoietin to patients undergoing chemoradiotherapy for stage IIB to stage IVA carcinoma of the cervix (GOG 191), radical hysterectomy plus tailored chemoradiotherapy versus chemoradiotherapy in stage IB2 carcinoma of the cervix (GOG 201), and chemoradiotherapy plus or minus tirapazamine in locally advanced cancer of the cervix (GOG 219). Even well-established standards of high-quality treatment are not always easily or consistently incorporated in standard practice such as timely treatment and use of brachytherapy.37
Although there have been several randomized trials in endometrial carcinoma, the role of radiotherapy remains poorly defined. Although the current FIGO staging system mandates lymphadenectomy, 2 recent trials showed no survival advantage when pelvic lymphadenectomy was performed.38,39 Adjuvant radiotherapy trials have demonstrated that most recurrences are confined to the pelvis, particularly the vagina. Clinical trials evaluating radiotherapy in endometrial carcinoma have generally demonstrated an approximate 70% decrease in risk of pelvic recurrence.40–43 However, the absolute risks of recurrence were very low in these trials because most of the patients entered had either low or low intermediate risk tumor characteristics. Most of the patients in these trials had grade 1 disease or less than 50% myometrial invasion. Patients with a higher absolute risk of recurrence may derive benefit from adjuvant external beam radiotherapy. In GOG 99, there was a consistent reduction in proportional risk; however, a large difference was noted in absolute risk between women with low intermediate risk (LIR) and high intermediate risk (HIR). The cumulative incidence of recurrence at 2 years was 19% in the HIR group, which was one third of the population, versus 4% in the low-intermediate-risk group.43 An unplanned subset analysis in the HIR group indicated that an absolute survival difference of as much as 15% to 20%, favoring the use of adjuvant pelvic radiotherapy may have occurred. There has not yet been an adequately powered trial to test the value of adjuvant RT in this group of patients.
The inconsistent quality of pathologic review is another major challenge in the effort to obtain generalizable conclusions from endometrial trials. After central pathologic review in the postoperative radiotherapy in endometrial cancer-1 trial, the percentage of patients with grade 1 disease increased to 21% from 69%. Similarly, the fraction of patients with grade 2 disease decreased from 68% at their home institution to 16% after central review. Nineteen percent of the patients in the postoperative radiotherapy in endometrial cancer-1 trial were ineligible because of the finding of grade 1 disease after central review.44 In this context, it has been very difficult to perform cross trial comparisons or to generalize the results of adjuvant radiotherapy trials because of these variations in surgical staging, central pathologic review, and eligibility criteria.
Ongoing RT trials in endometrial carcinoma are shown in Table 4. Important clinical research questions in uterine cancer radiotherapy include what is the most cost-effective means of determining regional disease extent? How inaccurate is pathology in the community? What is the role of external beam in higher intermediate risk and node-positive endometrioid carcinomas? What is the role of external beam radiotherapy in other histologies? Additionally, the optimal sequencing of chemotherapy and radiotherapy is unknown.
The performance of clinical trials will be advanced with the use of consistent language (ie, similar staging system and criteria), eligibility criteria that fit the research question, end points that matter, adequate statistical power, complete follow-up, and prompt publication of mature results. Comparative clinical trials are required to answer these questions. All oncologists treating women with gynecologic cancers should invest in participating in these important efforts.
This report describes a symposium held at the Radiation Therapy Oncology Group semiannual meeting in January 2011. Dr Arno Mundt spoke on image guidance and motion management in gynecologic radiation oncology. Dr Julie Schwarz from Washington University spoke on advances in imaging, and Dr Patricia Eifel spoke on clinical research in gynecologic radiation oncology: future questions.
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