Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

18. Pelvic and Para-aortic Nodal Target Delineation

Tony J. C. Wang • Cheng-Chia Wu • K. S. Clifford Chao

Pelvic and Para-Aortic Nodes – Highlights

New Contouring Guidelines

RTOG pelvic lymph node guidelines (IJROBP 2009) for high-risk prostate cancer have been updated. (PMID 18947938)

RTOG pelvic lymph node guidelines (IJROBP 2008 and IJROBP 2011) for endometrial and cervical cancers have been reported (PMID 18037584) with an update for cervical cancer nodal delineation. (PMID 20472347)

FIGURE 18-2. RTOG consensus guidelines for contours on pelvic lymph nodes in high-risk prostate cancer.

1. INTRODUCTION

• Definitive or adjuvant radiotherapy (RT) has contributed significantly to the successful management of urologic and gynecologic malignancies. Conventional RT is performed through either anteroposterior (AP) parallel-opposed fields or a four-field technique consisting of an anterior, a posterior, and two lateral portals. However, the use of conventional portals has been reported to result in incomplete coverage of the intended target volume and higher doses to normal tissues.13 Early studies by Bonin et al.4 and Pendlebury et al.5 reported inadequate coverage of the external iliac lymph nodes using standard irradiation fields in 45% and 62% of patients, respectively.

• The lack of conformality via conventional techniques is also associated with normal tissue complications. According to various criteria to classify the severity of the radiation side effects, severe complications may develop in 8% to 10% of patients treated with a conventional beam arrangement. The incidence of complications requiring surgical management is approximately 5%.6

• As chemoradiotherapy has become the integral therapeutic measure in either the definitive or postoperative setting, gastrointestinal (GI) complications have been the most significant concern other than hematologic side effects.

• Results from the early Radiation Therapy Oncology Group (RTOG) 79-20 study suggest that in a select group of patients, the use of extended fields covering the para-aortic lymph nodes is associated with better disease-free and overall survival compared with pelvic RT alone.7 However, when the lymph nodes are grossly enlarged, para-aortic lymph node RT combined with chemotherapy proved to be highly toxic in the RTOG 92-10 study. Although the acute hematologic toxicity was higher in patients receiving chemoradiotherapy than in those receiving RT alone, RTOG 92-10 clearly showed that 50% (15 of 30 patients) experienced grade 4 nonhematologic toxicity after therapy, and all 15 of those toxicities were bowel related. The cumulative incidence of late grade 3 and 4 toxicity was 34% at 36 months.8

• Techniques such as intensity-modulated radiation therapy (IMRT), which allows adequate target coverage in the pelvic and para-aortic lymph nodes while keeping the dose delivered to the critical organs such as the small bowel to a minimum, would be of tremendous interest and may permit combining high-dose RT and chemotherapy without prohibitive GI complications. Minimizing the volume of the GI tract inside the radiation field is pivotal to the potential improvement of the therapeutic ratio by IMRT.

• Portelance et al.9 demonstrated that IMRT for cervical cancer yields similar tumor coverage with superior normal tissue sparing compared with conventional beam arrangements. Similar findings were also reported in a study from the University of Chicago.10

• Guo et al.3 showed a significant reduction in volume of small bowel and rectum irradiated to 45 Gy with IMRT compared with conventional plans for endometrial cancer. In addition to the small bowel and rectum, Heron et al.2showed a reduction to bladder volume dose using IMRT.

• Mundt et al.11 found reduced grade 2 acute GI toxicities in patients who received IMRT compared to conventional whole pelvic radiotherapy (WPRT), 60% versus 91%, respectively, when treating for cervical and endometrial carcinoma.

• Kidd et al.12 reported the results of 452 cervical cancer patients treated with IMRT or non-IMRT with 50 Gy delivered to the pelvic lymph nodes and found reduced grade ≥3 bowel or bladder toxicities in favor of IMRT. There was also improved overall survival and cause-specific survival.

• Kachnic et al.13 reported the early toxicity results of RTOG 0529, a phase II trial of dose-painted IMRT with chemotherapy for anal carcinoma, in which elective pelvic nodes were treated to 45 Gy, and found low rates of grade 3 or higher GI toxicity of 7%. This was compared favorably to the 35% grade 3 and 4 GI toxicity, primarily diarrhea, reported in RTOG 9811.14

• The dosimetric advantage of IMRT may potentially improve the therapeutic outcome in patients with locally advanced cervical cancer, especially when the pelvic/para-aortic lymph nodes are grossly enlarged and a higher radiation dose is required.

• Patient- and tumor-related issues have hindered the acceptance of IMRT for patients with gynecologic malignancies.

º The first is related to the organ motion of the pelvic structures; for example, the uterus and cervix may shift as much as 4 to 5 cm on an AP projection, depending on whether the bladder and rectum are empty or full.1 Other studies regarding inter- and intrafraction organ motion have shown less shift while undergoing RT.15,16

• The second concern that hinders the widespread use of IMRT for gynecologic cancer is the lack of an objective description of pertinent lymph node locations in a three-dimensional (3D) projection. However, because the lymph node status is extremely important in determining the prognosis of gynecologic and urologic malignancies, IMRT plans must provide adequate coverage of the pelvic, para-aortic, and inguinal draining nodes when these are at risk.

2. IMAGING FOR PARA-AORTIC, PELVIC, AND INGUINAL LYMPH NODES

• Without computed tomography (CT) or magnetic resonance imaging (MRI), lymphangiography (LAG) can be an alternative to pelvic and para-aortic imaging.

• CT and MRI may be equally effective as LAG in detecting enlarged lymph nodes; however, small lymph nodes containing microscopic disease (clinical target volume [CTV]) are often difficult to identify using CT and MRI on the basis of size.

• Most institutions use CT to gather imaging data for IMRT treatment planning. Inconsistencies in visualizing unenlarged lymph nodes on pelvic and abdominal CT imaging could impose significant variations in target delineation among different physicians.

• Although LAG would greatly aid in determining the target volumes accurately, few institutions perform these technically difficult, uncomfortable, and time-consuming studies.

• In earlier Gynecologic Oncology Group (GOG) studies, LAG was considered the best option for detecting para-aortic nodal metastasis. The GOG studied the clinical–pathologic correlation of para-aortic lymph node involvement by CT, LAG, and ultrasonography in patients with stage IIB, III, and IVA cervical carcinoma. Of 264 patients evaluated, the LAG sensitivity was 79%, with a specificity of 73%. The sensitivity of CT and ultrasonography was 34% and 19%, with a specificity of 96% and 99%, respectively.17 However, LAG was also associated with some shortcomings in detecting metastatic internal iliac and presacral nodes, which are only occasionally seen.

• Scheidler et al.18 concluded that LAG, CT, and MRI perform equivalently in the detection of grossly enlarged metastatic pelvic lymph nodes from cervical cancer.

• Chao and Lin19 demonstrated that the nodal CTV can be better delineated by LAG-aided CT imaging. The combination of LAG, to demonstrate nodal texture, and CT, for spatial orientation, provides a better tool to delineate the CTV for the para-aortic, pelvic, and inguinal lymph nodes than relying solely on CT or MRI.

• Studies by Dinniwell et al. used MRI and ferumoxtran-10, a ultrasmall superparamagnetic iron oxide lymph node contrast agent, to define a population of pelvic lymph node for CTV. Patients with endometrial, cervical, prostate, or bladder cancer received MRI before and after contrast. Results from these studies suggest that usage of lymph node targeted contrast agent can better define pelvic lymph node population.20

3. PARA-AORTIC, PELVIC, AND INGUINAL NODAL TARGET VOLUME DELINEATION

• The lymph node locations are described relative to the aorta, inferior vena cava, common iliac, external iliac, and femoral vessels. Lymph nodes lying adjacent to the aorta and inferior vena cava from T12 to the aortic bifurcation are designated as para-aortic.

• Nodes adjacent to the common iliac vessels (from the aortic bifurcation to the branching of the internal iliac artery) are designated as common iliac.

• Nodes adjacent to the external iliac vessels and extending anteriorly above the iliopsoas muscle, as well as nodes lying posteriorly, including the obturator group, are deemed the external iliac group.

• Nodes located adjacent to the femoral vessels to the level of the inner edge of the ischial tuberosities are designated as inguinal nodes.

• Early studies by Chao et al. depicted one of the first 3D lymph node mappings to generate a nodal CTV guideline. With the aid of LAG, the distance from the vessel wall to the furthest lymph node was measured in each nodal region. Figure 18-1 depicts a measurement example, and Table 18-1 details the results.

• Because lymph nodes generally follow the path of the major blood vessels, contouring vessels followed by radial expansion may be a practical method to define the nodal CTV. However, Chao and Lin19showed that vessel contour expansion alone was not sufficient to cover the nodal areas fully and reasonably excludes normal tissue. Expanding the vessel contours (aorta plus 20 mm, inferior vena cava plus 10 mm, common iliac plus 15 mm, external iliac plus 20 mm, and femoral artery plus 20 mm) could still miss 17.7% of LAG-avid nodal volume. This approach, although simple, not only led to inadequate CTV coverage, but also resulted in the inclusion of a substantial amount of normal tissue inside the CTV.

• To assist radiation oncologists in correctly delineating the nodal target volume, Chao and Lin19 reported early guidelines to determine the spatial orientation of the para-aortic, pelvic, and inguinal nodes on the basis of the relationship of the nodal groups to nearby anatomic structures with the aid of bipedal LAG on CT images (Table 18-2). Newer consensus guidelines have been published and are discussed in the following sections.

• Given that nodal volume delineation is time consuming, Young et al. hypothesized that atlas-based segmentation (autocontouring) can lead to time-saving and more consistent contours among physicians. Using data from 15 postoperative endometrial cancer patients, a reference anatomy atlas has been created according to the RTOG 0418 trial using commercially available software. Three radiation oncologists corrected the autocontours and delineated the manual nodal contours under timed conditions while unaware of the other contours.21

• The results show that autocontouring leads to increased consistency and decreases time consumption when contouring the nodal target volumes for adjuvant treatment of endometrial cancer (see figure 1 of Ref. 21).

4. CONSENSUS GUIDELINES FOR THE FEMALE PELVIS

• Advances in IMRT have decreased the amount of irradiation in normal organs such as small bowel, rectum, and bone marrow in whole pelvic RT for gynecological malignancies. Given these advancements, the need for guidelines for target delineation has increased.

• In 2008, the RTOG led an international collaboration to define an atlas of target definition for postoperative pelvic RT for endometrial and cervical cancers. The groups included RTOG, the National Cancer Institute of Canada, the European Society of Therapeutic Radiology and Oncology, and the American College of Radiology Imaging Network. The representatives of the groups were asked to obtain formal endorsement of the final atlas.22 Subsequently, guidelines for the definitive treatment of cervical cancer were updated in 2011.23 The results are discussed below with an emphasis on pelvic lymph node delineation.

• Table 18-3 shows the consensus CTV for adjuvant RT for cervical and endometrial cancer. Target sites include the common iliac lymph nodes, external iliac lymph nodes, internal iliac lymph nodes, upper vagina, parametrial/paravaginal tissue, and presacral lymph nodes.

FIGURE 18-1. Cross-sectional computed tomography (CT) images demonstrating technique to measure distance of LAG-avid lymph nodes to adjacent vessel and nodal CTV delineation at various anatomic levels. (A) Furthest distance from lymph node to vessel wall determined on a Voxel-Q computer (Marconi, Cleveland, OH). (B) Para-aortic lymph node CTV. (C) Common iliac lymph node CTV. (D) External iliac CTV, including lateral group. (E) External iliac CTV, including medial (obturator) group. (F)Inguinal lymph node CTV. CTV depicted by thick orange line. Small bowel demarcated by thin magenta, large bowel by thin blue, rectum by thin dark purple, bladder by thin turquoise, and uterus by thin yellow-green line. (From Chao KSC, Lin M. Lymphangiogram-assisted lymph node target delineation for patients with gynecological malignancies. Int J Radiat Oncol Biol Phys 2002;54:1147–1152.)

• The common iliac lymph nodes are delineated from 7 mm below the L4–L5 interspace to the level of the bifurcation of the common iliac arteries into the external and internal iliac arteries.

• The external iliac lymph nodes are delineated from the level of the bifurcation of the common iliac artery into the external artery to the level of the superior aspect of the femoral head where it becomes the femoral artery.

• The internal iliac lymph nodes are delineated from the level of the bifurcation of the common iliac artery into the internal artery, along its branches (obturator, hypogastric) terminating in the paravaginal tissues at the level of the vaginal cuff.

• The presacral lymph nodes include lymph node region anterior to S1 and S2 region.

5. CONSENSUS GUIDELINES FOR THE MALE PELVIS

• Pelvic lymph node radiation is an important part of treatment for high-risk and locally advanced prostate cancer patients. The problem is that there is a significant difference in opinion regarding the appropriate pelvic lymph node volumes to be treated. This led to a consensus on pelvic lymph node CTVs for radiation therapy for high-risk prostate cancer patients in 2009.24

• The three main drainage patterns for the prostate are24,25

º Cranially to the internal iliac lymph nodes.

º Laterally to the external iliac lymph nodes.

º Posteriorly to the subaortic aspect of the presacral lymph nodes S1–S3.

• The recommended guidelines for contours on pelvic lymph nodes in high-risk prostate cancer are described below:

º Commence contouring the pelvic CTV lymph node volumes at the L5–S1 interspace (the level of the distal common iliac and proximal presacral lymph nodes) (see Fig. 18-2A).

º Place a 7-mm margin around the iliac vessels connecting the external and internal iliac contours on each slice, carving out bowel, bladder, and bone (see Fig. 18-2B,C).

º Contour presacral lymph nodes (subaortic only) S1–S3, posterior border being the anterior sacrum and anterior border approximately 10 mm anterior to the anterior sacral bone carving out bowel, bladder, and bone (see Fig. 18-2A,B).

º Stop external iliac CTV lymph node contours at the top of the femoral heads (bony landmark for the inguinal ligament) (see Fig. 18-2D).

º Stop contours of the obturator CTV lymph nodes at the top of the pubic symphysis (see Fig. 18-2E).

FIGURE 18-2. Representative pelvic lymph node clinical target volume (CTV) contours from consensus CT. (A) Common iliac and presacral CTV lymph node volumes (L5/S1). (B) External, internal, and presacral CTV lymph node volumes (S1–S3). (C)External and internal iliac CTV lymph node volumes (below S3). (D) End of external iliac CTV lymph node volumes (at top of femoral head, boney landmark for the inguinal ligament). Note: part E showing obturator CTV lymph node volumes is not reproduced here. (Reprinted from: Lawton CA, Michalski J, El-Naqa I, et al. RTOG GU radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2009;74(2):383–387, with permission.)

• For the convenience of the reader, we have reproduced four of the RTOG contours, slightly digitally enhanced for easier viewing (Fig. 18-2).

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13. Kachnic LA, Tsai HK, Coen JJ, et al. Dose-painted intensity- modulated radiation therapy for anal cancer: a multi-institutional report of acute toxicity and response to therapy. Int J Radiat Oncol Biol Phys 2012;82(1):153–158.

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19. Chao KSC and Lin M. Lymphangiogram-assisted lymph node target delineation for patients with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2002;54(4):1147–1152.

20. Dinniwell R, Chan P, Czarnota G, et al. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2009;74(3):844–851.

21. Young AV, Wortham A, Wernick I, Evans A, Ennis RD. Atlas-based segmentation improves consistency and decreases time required for contouring postoperative endometrial cancer nodal volumes. Int J Radiat Oncol Biol Phys 2011;79(3):943–947.

22. Small W Jr., Mell LK, Anderson P, et al. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer. Int J Radiat Oncol Biol Phys 2008;71(2):428–434.

23. Lim K, Small W Jr., Portelance L, et al. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol Biol Phys 2011;79(2):348–355.

24. Lawton CA, Michalski J, El-Naqa I, et al. RTOG GU radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2009;74(2):383–387.

25. Gil-Vernet JM. Prostate cancer: anatomical and surgical considerations. Br J Urol 1996;78(2):161–168.